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

What Makes the Ketamine-Based Drug for Depression So Different?

On Tuesday (March 5), the U.S. Food and Drug Administration (FDA) approved a ketamine-like nasal spray for patients with depression who haven’t responded to other treatments.

But what makes this newly approved treatment so different?

The drug, called Spravato and made by Janssen Pharmaceuticals, contains the active ingredient esketamine. This substance has the same molecular formula as ketamine but a different chemical structure. (In other words, it contains the same type and number of elements but in a different configuration.) Ketamine is typically used as an anesthetic, but it’s also been used as an illicit party drug.

One reason experts are excited about the nasal spray is that its effects can be seen within several hours to days. Other antidepressants, meanwhile, can take weeks to start working

Antidepressants work by regrowing brain cells and the connections between them, and ketamine appears to have the same effects, said David Olson, an assistant professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. But, these effects likely start much sooner than with other antidepressants, he said.

Still, it’s not entirely clear how the drug works.

Ketamine-like drugs are “dirty”, meaning they likely hit a variety of targets in the brain, Olson told Live Science. “There are a lot of very interesting hypotheses out there, [and] many of them are probably partially valid.”

One idea is that ketamine treats depression by blocking a neurotransmitter called glutamate from binding to the NMDA receptor, and stopping signals from cascading across the brain, Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, told Live Science.

Glutamate is a chemical that brain cells use to send signals to other brain cells. But high levels of it can cause over-excitement in the brain, which can, in turn, damage brain cells.

A more controversial idea is that ketamine binds to opioid receptors, causing a release of naturally occurring opioids in the body. Schatzberg and his team published a small study on this last summer in which they gave patients with depression ketamine twice — once after receiving an opioid-blocking drug, and once after receiving a placebo in place of the opioid blocker. The two treatments took place about a month apart, and neither the participants nor the researchers knew whether patients received the opioid blocker or the placebo. The study found that the patients responded well to the ketamine treatment if they didn’t receive the opioid-blocking drug, but ketamine had no effect on those that did, suggesting an opioid-like role.

This hypothesis has some experts concerned about ketamine-based drugs as a depression treatment.

“My concern about this compound is that it is a disguised form of opiates,” said Dr. Mark George, a distinguished professor of psychiatry, radiology and neurosciences at the Medical University of South Carolina. While George said he is “overjoyed” for the prospect of a new treatment option, “I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.”

If this is the mechanism that ketamine acts through to treat depression, its effects won’t last and people might develop a tolerance to the drug, possibly even becoming addicted, George told Live Science. But if its antidepressant effects come from other mechanisms, such as blocking the NMDA receptor, then “that’s good,” he said.

Olson, however, said that he is less convinced by the opioid hypothesis and thinks more work needs to be done before ringing the alarm bells.

What’s more, the new drug will see limited use. The medication comes with a risk of sedation and dissociation, such as difficulty with judgment, attention and thinking. Because of that, the nasal spray was approved to be used only under a “restricted distribution system,” according to a statement from the FDA.

This means that only patients with severe depression who haven’t responded to at least two antidepressant treatments can receive the drug. In addition, the treatment is administered only in doctor’s offices, and patients must stay in the office and be monitored for several hours after receiving the treatment.

Ultimately, despite some potential problems with the newly approved drug, experts are hopeful it will come through strong.

“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases,” Olson said. “Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”



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Listening to ketamine

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CREDIT: VIDEO PRODUCED BY HUNNI MEDIA FOR KNOWABLE

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

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

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

Depression, fast and slow

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

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

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

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

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

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

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

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

Seeking answers in neural wiring

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

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

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

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

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

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

Circuit training

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

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

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

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

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

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

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

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

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

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

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

Plastic synaptic remodelers

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

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

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

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

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

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

Dissecting depression

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

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

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

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

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

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

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

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

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

Ketamine in teens?

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

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

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

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

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

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

Not just a quick fix

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

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

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

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

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

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

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

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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

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.

From Popular Anesthetic to Antidepressant, Ketamine Isn’t the Drug You Think It Is

An hour before we spoke, Darragh O’Carroll, an emergency room physician from Hawaii, had just given an elderly patient a sedating shot of ketamine. The man had pneumonia and was acting confused and fidgety, making him hard to treat.

“Not only it was a pain control for him when I was putting needles into his neck, but it also kept him still,” O’Carroll says. “And with very minimal risk of lowering his blood pressure.”

Ketamine’s use as an anesthetic — and not as a party drug — is widespread, though not commonly known. In fact, the World Health Organizationestimates ketamine is the most widely used anesthetic in the world and keeps it on their list of essential medicines, a category of drugs that all developed countries should have on hand.

O’Carroll has described ketamine as his “favorite medicine of all time” in an article for Tonic, not only because the anesthetic is incredibly safe and effective, but also because of its versatility. It’s most widely used in surgery, but could also help treat severe asthma, chronic pain, and may even possess anti-tumor properties. In the last two decades, ketamine has also emerged as a potent antidepressant, able to treat symptoms of some mental illnesses in less than 72 hours.

“I think the more research that goes into ketamine, the more uses that we find for it,” O’Carroll says.

From PCP to Painkiller

Ketamine’s story begins with a drug called PCP. Yes, that PCP — phencyclidine or so-called “angel dust,” a drug that when smoked can cause a trance-like state, agitation and out-of-body hallucinations. After it was first synthesized by medicinal chemist Victor Maddox in 1956, the drug was briefly approved as an anesthetic by the FDA for its sedative properties. In tests with a wild rhesus monkey, for example, researchers put their fingers in the previously aggressive animal’s mouth and watched its jaw remain slack.

But while it was safe and effective for pain relief, the side effects of PCP soon became too obvious to ignore.

Some patients under the influence of PCP would feel like they lost their arms or legs or that they were floating in space. It could also cause seizures and delirium. Scientists began seeking a shorter-acting anesthetic without convulsant properties. In 1962, chemistry professor Calvin Stevens discovered a PCP analogue that fit the bill: ketamine.

Ketamine is a potent, sedating painkiller that can cause amnesia and is mostly used in surgery and veterinary medicine. During the Vietnam Invasion, ketamine saw widespread use in the U.S. military because it has several advantages over opioids. First, unlike morphine, ketamine doesn’t suppress blood pressure or breathing. It also doesn’t need to be refrigerated, making it useful in the field or in rural areas that don’t have access to electricity.

Ketamine’s benefits extend beyond use as an anesthetic, though — in some cases it can serve as a balm for the mind as well. A 2008 analysis found that burn victims who were given ketamine were less likely to develop symptoms of post-traumatic stress disorder, even if their injuries were more severe. Those findings have been replicated, such as a 2014 clinical trial of 41 patients, who saw their PTSD symptoms diminish within 24 hours, an effect that lasted for two weeks.

“When somebody gets one of their limbs dramatically blown off or is shot in the face, it’s a very traumatic event,” O’Carroll says. In such a situation, giving ketamine not only provides instant pain relief, it could prevent long-lasting trauma.

Because its chemical structure is so similar to PCP, ketamine can still give lucid hallucinations, such as feeling that your mind has separated from the body — a dissociative state users sometimes call a “K-hole.” One recent study based on users’ written reports even indicated that this kind of experience might be a close analogue to a near-death experience. However, these dissociative states only happen at high doses — the amount of ketamine used to for surgery and to treat depression is typically much lower.

But ketamine’s side effects are less common and easier to manage than PCP. In fact, ketamine is one of the safest drugs used in medicine today and can even be given to young children. For example, ketamine was used to sedatethe boys’ soccer team trapped in a cave in Thailand last year. Putting the kids in a tranquilized state made it easier to rescue them, and ketamine is safer than the opioids or benzodiazepines that are also commonly used as sedatives.  

Ketamine as Antidepressant

But it wasn’t until the 1990s that what could turn out to be ketamine’s most important function was discovered. A team from Yale University School of Medicine was examining the role of glutamate, a common neurotransmitter, in depression, and discovered something remarkable: ketamine could rapidly relieve depression symptoms.

“To our surprise, the patients started saying, they were better in a few hours,” Dennis Charney, one of the researchers, told Bloomberg. This rapid relief was unheard of in psychiatry.

Glutamate is associated with neural plasticity, our brain’s ability to adapt and change at the level of the neuron. Ketamine blocks certain glutamate receptors, but not others, and the end effect could be to promote the growth of new neurons while protecting old ones. This could explain how ketamine can help reset the brain, though the theory hasn’t yet been definitively proven.

The prescription meds currently on the market for depression have some major drawbacks. Drugs like Prozac or Wellbutrin can take a few weeks or months to kick in while worsening symptoms in the short term — not a good combination, especially for someone who is extremely depressed, or even suicidal.

It took around a decade for mainstream science to take notice of these early ketamine-depression studies. But once it did, ketamine clinics began popping up all across North America, offering fast relief for depression, anxiety and other mental illnesses. Patients are given an infusion — an IV drip that lasts about an hour — and many people, but not everyone, have seen rapid relief of their symptoms.

Suddenly, ketamine infusions became trendy, though the science to back up some of the medical claims is still inconclusive, according to STAT. However, ketamine infusions are rarely covered by insurance, although that is changing. A typical session can run $700, with many patients taking six sessions or more. But many of these patients have so-called treatment-resistant depression. They’ve tried other medications or therapies without success and some see ketamine as a last resort.

Steven Mandel, a clinical psychologist and anesthesiologist, has used ketamine on patients since it first came on the market around 50 years ago. In 2014, he began using it for patients with depression and opened Ketamine Clinics of Los Angeles, one of the oldest and largest clinics in the country. They’ve done over 8,000 infusions so far.

“Our success rate is better than 83 percent,” Mandel says. For his clinic, success means a 50 percent improvement of depression symptoms for longer than three months.

Ketamine’s success as an antidepressant couldn’t help but attract the attention of major pharmaceutical companies as well. In 2009, Johnson & Johnson began developing their own version of the drug they called esketamine. Rather than an infusion through a vein, it’s dispensed through a nasal spray. The FDA approved their formulation in early March. It was thefirst drug in 35 years to fight depression using a different approach than traditional drugs.

“Esketamine is a giant step forward,” Mandel says. “It means we’re not going to be demonizing mind-altering substances used for therapeutic purposes. It opens the door to research on LSD, on psilocybin, on MDMA and many other agents that could possibly relieve a great deal of suffering.”

But many clinicians have raised concerns about long-term side effects, such as heart and bladder toxicity. Others have been critical of esketamine, saying there isn’t enough data yet to suggest the drug is safe or effective. Husseini Manji, a neuroscientist who helped develop the drug for Johnson & Johnson at their subsidiary Janssen, has pushed back against these claims.

“When you line up the totality of the studies, it was really an overwhelming amount of data that was all in the same direction,” Manji says in a call. Though just two of the five late-state clinical trials showed significant results, the changes in mood in the three that fell short were “almost identical in magnitude” to the others, Manji says. It was enough for the drug to meet standards for FDA approval.

We can probably expect other ketamine-related drugs to come to market soon. ATAI Life Sciences, a company funding research on the use of magic mushrooms for depression, is developing their own ketamine depression drug. The pharmaceutical company Allergan also developed rapastinel, another ketamine-like drug, though it failed to show any real benefits for patients in later trials. Manji says this is unfortunate for people who could be helped by these kinds of drugs.

“From a patient standpoint, we were hoping it would work,” he says, even though he was not involved in rapastinel’s development. “But sometimes if you really haven’t got the mechanism right and you haven’t really threaded the needle, then sometimes you don’t see these results.”

Drug of Abuse?

Even though ketamine’s medical uses are well-established, most people have only heard of ketamine in the context of a party drug. Because of this bad reputation — and what’s perceived as growing misuse of the drug — several countries, such as China and the UK, have tried to place greater restrictions on ketamine. This would make it harder to study and more expensive in clinical use.

“If it was to ever be rescheduled, places that would be first affected would be you know places that need it most,” O’Carroll says. The WHO has asked at least four times for countries to keep access to ketamine open. “The medical benefits of ketamine far outweigh potential harm from recreational use,” Marie-Paule Kieny, assistant director general for Health Systems and Innovation at WHO, said in 2015.

So far, no countries have put greater restrictions on ketamine, and that’s probably a good thing. Ketamine has a rich history, but its future is still being written.

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



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.

VA to offer new ketamine-based nasal spray to help combat depression

The newest FDA-approved medication to treat severe depression, a nasal spray based on the anesthetic (and misused hallucinogenic party drug) ketamine, will soon be available to veterans treated within the Department of Veterans Affairs.

In a move that may help thousands of former service members with depression that has not improved with other treatments, VA officials announced Tuesday that the department’s doctors are now authorized to prescribe Spravato, the brand name for esketamine, a molecular variation of ketamine.

The decision to offer a drug hailed by many as a breakthrough in treatment for its speedy results — often relieving symptoms in hours and days, not weeks — shows the VA’s “commitment to seek new ways to provide the best health care available for our nation’s veterans,” Secretary Robert Wilkie said in a release.

“We’re pleased to be able to expand options for Veterans with depression who have not responded to other treatments,” Wilkie added.

The treatment will be available to veterans based on a physician’s assessment and only will be administered to patients who have tried at least two antidepressant medications and continue to have symptoms of major depressive disorder.

An estimated 16 million Americans have had at least one major episode of depression, and of those, 1 in 3 are considered treatment-resistant. In the veteran population of 20 million, the estimated diagnosis rate of depression is 14 percent — up to 2.8 million veterans. Between one-third and half of those veterans may be treatment-resistant.

The lack of effective medications for difficult-to-treat patients prompted the Food and Drug Administration to place esketamine on a fast track, expediting its review of the drug to ensure that it went to patent as soon as safely possible, according to administration officials.

“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process, including a robust discussion with our external advisory committees, were important in our decision to approve this treatment,” said Dr. Tiffany Farchione, acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products, in a release.

As with any other medication, there are risks. Spravato carries a boxed warning for side effects that include misuse, the reason it is administered under a doctor’s supervision. The list of side effects includes sedation and blood pressure spikes and disassociation, such as feelings of physical paralysis and out-of-body experiences. It also can cause suicidal thoughts and behaviors.

Acknowledging the dangers, FDA made esketamine available only through a restricted distribution system.

A veteran prescribed Spravato would inhale the nasal spray at a medical facility while under supervision of a medical provider, and would be monitored for at least two hours after receiving the dose. A typical prescription includes twice-weekly doses the first month, followed by a single dose weekly or biweekly as needed. Spravato cannot be dispensed for home use.

Spravato is made by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is the first major antidepressant medication to hit the market in 30 years.



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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

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Twitter feed Ketamine – Ablow

Ketamine Seems to Ease Depression. We’ll Soon See What Else It Does.

Clinical trials are not enough to prove any drug is safe and effective – especially one that could be as widely used as Johnson & Johnson’s depression drug esketamine, a slightly altered form of the street drug ketamine. The FDA approval process is a balancing act, weighing safety and efficacy testing against the need to get potentially life-saving drugs out as soon as possible.

An advisory panel to the FDA decided this month that the benefits outweigh the risks, and approval is expected soon. But scientists who study depression say there’s a lot more to learn about esketamine’s long-term effects.

While best known as a recreational drug, ketamine has been used since the 1970s as an anesthetic, in doses much higher than what’s likely to be given to depression patients. The trials so far seem to show that the drug is not highly addictive, according to a story in the medical website STAT. But time will tell.

The most promising clinical trials followed people whose depression had been resistant to conventional therapy. Fifty percent of patients improved when given conventional therapy plus a placebo, as compared to 70 percent who got conventional therapy and esketamine.

Taking the drug will be a lot more complicated than taking Prozac. It’s been formulated so that it can be delivered as a nasal spray, but people have to get the drug at a doctor’s office, and they won’t be allowed to drive for at least 24 hours, said Gerard Sanacora, a Yale University psychiatrist who has been involved in the clinical trials.

He said he believes there’s potential for benefit, because the drug works for some people who get no relief from conventional treatments and because works faster, which might even prevent suicide. But there’s a lot more to learn about the drug’s potential long-term consequences. So far it looks like people will get two treatments a week to start, then one for maintenance. But scientists don’t know whether it can be tapered down further, or discontinued, and whether there’s a risk for relapse, he said.

Sanacora said that ketamine is based on a very different model of how depression works. Standard therapy is based on the principle that depression is a chemical imbalance involving the transmitting chemical serotonin. But an alternative view started to take shape in the 1990s that depression was more of a problem with the connections between neurons, triggered by chronic stress and mediated by something called the glutaminergic system.

Because ketamine interacts with this system, researchers started testing it as a depression drug. Although it seems effective, there’s still no agreement on how depression actually works – and there is some concern that it might work very differently in different patients.

Ketamine can affect cardiovascular health, and in the short term can cause patients to lose their sense of their bodies’ position in space – the sense of proprioception. They sometimes feel their arms are floating.

That hasn’t stopped people from flocking to clinics to get treated with IV ketamine infusions for depression and other problems. This is legal because the drug is approved for anesthesia, and prescribers can use it off-label for other purposes. An investigation by the medical website STAT raised concerns that clinic staff didn’t have the necessary expertise, and there was considerable marketing hype in many cases. The infusions cost between $350 and $1,000 each, and can go on for five or six treatments.

Another red flag popped up last week when the Boston Globe ran a storyabout three women who claim to have been sexually abused by psychiatrist Keith Ablow – a frequent commentator for Fox News. The Globe reported that Ablow was treating the women with ketamine, and one expert cited in the lawsuits said a patient had become “very dependent on this medication and dependent on Dr. Ablow to supply it.”

Ablow’s Twitter feed is full of positive stories about ketamine in places such as Reader’s Digest, followed by a phone number to call for a “free ketamine screening.” The allegations illustration that it’s not just patients that will need to be tracked for abuse, but the doctors as well.

On the positive side, FDA approval would give patients who want the drug a standardized treatment that would be covered by many insurance plans. Approval also creates an opportunity to collect data on longer-term use. (An earlier column exploring the promise of big data in medicine points out that clinical trials are often not long-running enough or big enough to catch even deadly side effects.)

Yale’s Sanacora thinks of the next series of trials as Phase 4. Sanacora also brought up what he poignantly called the “Flowers for Algernon” effect, referring to the short story in which the main character, Charlie Gordon, is treated for an intellectual disability. The treatment works, but eventually wears off, leaving Charlie back where he started. The disappointment makes for a tragic tale. An arc like this would be the last thing depression patients need – though if no other treatment is helping, it might be a risk worth taking.

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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 Virginia Link

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 Virginia Link

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.”

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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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What is interesting for the above articles is the Magnesium and copper components associated with Depression.

The most common biomarkers found are generally related to the regulation of lipid metabolism, control of immunoinflammatory response, control of vascular function, inter and intra-cellular communication. We additionally found that biomarkers related to nutrient sensing and proteostasis are related to LLD. Altogether, these studies suggest that there are core abnormalities, which are present in the first depressive episode, continue over mid-life and late-life, and are persistent even after successful antidepressant treatment. This view is consistent with the presence of biological “scars” in depression that render individuals with major depression , age, more vulnerable to systemic illness, disability, cognitive impairment and other negative health outcomes, which are not fully ameliorated despite successful antidepressant treatment . Robust machine learning techniques showed that three proteins (C-peptide, fatty acid-binding protein, and ApoA-IV) have a very high accuracy at discriminating individuals with remitted LLD compared to never depressed control participants. In fact, our study showed the highest discriminatory power of any previous studies, including those for schizophrenia, bipolar disorder or other common mental illnesses .

http://software.broadinstitute.org/gsea/msigdb

. LLD is associated with significantly higher levels of pro-inflammatory and lower levels of anti-inflammatory markers, reduced neurotrophic support, and higher levels of oxidative stress markers and activity of glycogen synthase kinase

I nflammation is a key pathway in the initiation and progression of coronary heart disease (CHD), and inflammatory biomarkers such as C-reactive protein (CRP) and interleukin-6 (IL-6) have shown consistent associations with incident CHD events (1). In recent years, myeloperoxydase (MPO) has drawn growing attention as a new inflammatory biomarker of CHD risk (2–4). Myeloperoxydase is an enzyme produced by activated leukocytes during the innate immune response that catalyzes the formation of reactive oxidant species. It is present in human atherosclerotic plaques and exhibits a variety of proatherogenic properties (5). Increased inflammation is a key mechanism through which several risk factors increase CHD risk (6). Depression is a risk factor for CHD (7), and whether increased inflammation is involved has attracted considerable interest (8). A role of inflammation in depression was first proposed by Smith in 1991 (9). Since then, several studies have reported a link between major depressive disorder (MDD) or depressive symptoms and a variety of inflammatory and immune biomarkers (10 –15). However, others have found no independent association (16) or mixed results (17–19), and one study even found lower levels of inflammatory biomarkers in depressed cardiac outpatients (20). It is increasingly recognized that the relationship between depression and inflammation is more complex than initially conceived (21). Depression may cause inflammation through altered neuroendocrine function and central adiposity (22). However, depression may also be a consequence of inflammation, since a pathogenic role of inflammatory cytokines in the etiology of depression has been described (23). Although given less consideration, a third possibility is that depression is a marker of some other underlying dimension that is separately linked to depression and inflammation. Recently, it has been proposed that such underlying factor could be a specific genetic makeup (24,25). Evidence for a common genetic substrate for depression and inflammation would be of substantial scientific and clinical interest, because it would suggest that a common biological pathway links these two conditions. We found that MDD is associated with higher levels of inflammation and that this association is particularly robust for MPO, an inflammatory biomarker that was never studied before in relation to depression. However, we also found evidence for genetic confounding in this association. Our results are consistent with the hypothesis that there is a common genetic substrate linking MDD and inflammation, suggesting that these two phenotypes share a common pathophysiological mechanism. MPO, Other Inflammatory Markers, and Depression Myeloperoxydase is an enzyme of the innate immune system, which exhibits a wide array of proatherogenic features (5,34). Myeloperoxydase is secreted upon leukocyte activation, contributing to innate host defenses. However, it also increases oxidative stress, thereby contributing to tissue damage during inflammation and atherogenesis. Myeloperoxydase generates numerous reactive oxidants that cause lipid peroxidation, posttranslational modifications to target proteins, and decrease of nitric oxide bioavailability, resulting in oxidation of LDL and apolipoprotein A1, protein carbamylation, and endothelial dysfunction (5,35,36). Transgenic mice containing the human MPO gene show significantly larger atherosclerosis buildup than the wild-type (34,37). In humans, individuals with total or subtotal MPO deficiency, a defect with a frequency of 1 in every 2000 to 4000 whites, are less likely to develop cardiovascular diseases, and those harboring a promoter polymorphism associated with a twofold reduction in MPO expression appear cardioprotected (5,38 – 40). Consistent with these proatherogenic properties, MPO has received growing attention as a novel risk marker for future cardiovascular events (2– 4). Oxidative stress has also been linked to neuronal degeneration in the central nervous system (41,42). Myeloperoxydase is both expressed and enzymatically active in the human brain (43,44) and is associated with Alzheimer’s disease (44). Previous studies have described abnormalities of oxidant-antioxidant systems in MDD suggestive of higher oxidative stress. For example, elevated levels of antioxidant enzymes, particularly superoxide dismutase (SOD), and biomarkers of oxidation, such as malondialdehyde, were found in plasma, red blood cells, or other peripheral tissues of acutely depressed MDD patients compared with control subjects (45– 47). In some cases (46,47), but not others (45), these abnormalities were reduced with antidepressant treatment. Superoxide dismutase coenzyme concentrations are also higher in postmortem brain tissue (prefrontal cortex) of MDD patients than in control brains (48).

MOOD FOOD Project

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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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NEW VARIATION OF KETAMINE TO BE APPROVED BY FDA FOR TREATMENT OF DEPRESSION

“The biggest breakthrough in depression treatment since Prozac”

  • 6 FEBRUARY 2019
New variation of ketamine to be approved by FDA for treatment of depression

Back in July of 2017, the world’s first ketamine trial for depression proved to be “incredibly effective” in curing elderly patients. The drug, often referred to as Special K, is a popular substance found clubland culture, but recent breakthrough studies and the development of chemical variations of ketamine has shown that the drug is a powerful tool that can help save lives and allow people to live life to the fullest potential.

According to Bloomberg, the Food and Drug Administration (FDA) has cleared the way for the first drug based on ketamine, from Johnson & Johnson, to gain approval as soon as March 2019. The ketamine variant, called esketamine, may very well become the first-ever rapid-acting antidepressant for suicidal patients and “treatment-resistant depression”. While physicians are still unsure about the long term effects of the drug and more trials need to be conducted in order to get to the root of its effectiveness, many doctors think esketamine may be “the biggest breakthrough in depression treatment since Prozac”.

The long-form story published in Bloomberg tells the stories of multiple people who have benefited from ketamine treatment and how the rapid development of this new miracle drug is being used to combat the skyrocketing rate of suicide in the United States (up 33 per cent in the last 20 years).

The drug esketamine provides “a quick molecular reset button for brains impaired by stress or depression”. Initially developed as an intravenous drug, Johnson & Johnson has developed a nasal solution that has the same effect. The initial study of the drug involved 68 people at high risk that were all antidepressants and other treatment – no placebos were used on actively suicidal patients. Of those who were given esketamine, 40 per cent were deemed “no longer at risk of killing themselves within 24 hours”.

As physicians and investors race to find out more about this supposed miracle drug, concerns remain that a new abuse crisis – similar to that of the current opioid crisis – may arise following federal approval of the substance.

Check out the captivating story behind these successful studies here

Learn more about ketamine’s colorful clubland history here.

Find out how we survived an unconventional, silly, hilarious and definitely brilliant musical about ketamine here.

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BDNF-VEGF interplay key to rapid antidepressant actions A study in Biological Psychiatry investigates the mechanisms of fast-acting antidepressants E-MAIL

Philadelphia, January 31, 2019 — A study by researchers at Yale University reveals a complex interplay of two different growth factors in the rapid and long-lasting antidepressant effects of ketamine. The study, published in Biological Psychiatry, reports that the antidepressant-like actions of brain-derived neurotrophic factor (BDNF) require the release of vascular endothelial growth factor (VEGF).

“Surprisingly, the reciprocal relationship was also observed, indicating that BDNF-VEGF interdependence plays a crucial role in the actions of rapid-acting antidepressants,” said senior author Ronald Duman, PhD.

Ketamine requires the release of both BDNF and VEGF to produce its rapid antidepressant effects, but the connection between the two growth factors–which have different functions and act through different mechanisms–was unknown.

Using mice to model behaviors of depression, the researchers investigated the interaction of BDNF and VEGF. Administering BDNF or VEGF to a brain region implicated in depression, the medial prefrontal cortex (mPFC), produces rapid and long-lasting antidepressant-like actions similar to those of ketamine. In the study, Dr. Duman and colleagues found that removing VEGF from the mPFC prevented the antidepressant-like effects of BDNF in mice. When they performed similar experiments but instead blocked BDNF, the antidepressant-like effects of VEGF were prevented.

Deeper analysis using neuron cultures to examine how the two factors depend on each other revealed that BDNF signaling stimulates VEGF release in neurons and requires VEGF to produce its neurotrophic effects. Conversely, VEGF stimulates the release of BDNF and requires BDNF signaling to produce its neurotrophic effects.

“This observation may have important clinical implications. VEGF inhibitors are widely used to treat various cancers and can be associated with increased risk for depression and cognitive impairments sometimes called the ‘fog of chemotherapy’.

“Since most antidepressant effects are mediated by BDNF, and therefore VEGF, how should we treat these forms of depression and cognitive impairments? The answer to this question may draw us to BDNF-independent effects of antidepressants and new insights into the biology and treatment of depression,” said John Krystal, MD, Editor of Biological Psychiatry.

The results provide the first evidence that reciprocal interdependence of BDNF and VEGF plays a crucial role in their rapid antidepressant-like effects, revealing key mechanisms of ketamine, which requires both BDNF and VEGF. The findings also highlight avenues of research to better understand how each of the factors may affect a person’s risk of depression or their response to antidepressant drugs.

Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor  < Article

Major depressive disorder is a widespread debilitating illness, affecting approximately 17% of the population in the United States and causing enormous personal and socioeconomic burden (12) . Conventional antidepressants, notably monoamine reuptake inhibitors, take weeks to months to produce a therapeutic response and have limited efficacy, as approximately one third of patients with depression fail to respond to typical antidepressants and are considered treatment resistant (3) . Recent studies demonstrate that a single subanesthetic dose of ketamine, an N -methyl-D-aspartate receptor (NMDAR) antagonist, produces rapid (within hours) and sustained (up to a week) antidepressant actions even in patients with treatment-resistant depression(45) ; similar rapid and long-lasting effects are observed in rodent models (67) .

Although the mechanisms underlying the pathophysiology of major depressive disorder and the therapeutic actions of ketamine remain unclear, growing evidence supports a neurotrophic hypothesis of depression and antidepressant response 8910 . This hypothesis is based on evidence that reduced neurotrophic factor levels, notably brain-derived neurotrophic factor (BDNF) and/or vascular endothelial growth factor (VEGF), are tightly linked with neuronal atrophy in brain regions implicated in major depressive disorder, including the prefrontal cortex (PFC) and hippocampus 8910 . BDNF and VEGF are two completely different pleiotropic growth factors that bind to and activate different tyrosine kinase receptors, neurotrophic receptor tyrosine kinase 2 (TRKB) and fetal liver kinase 1 (FLK1) (also known as VEGF receptor 2), respectively, that have unique as well as overlapping signaling pathways 111213 . In support of this hypothesis, neuroimaging studies have consistently reported decreased volume of the PFC and hippocampus in patients with depression (1415) ; neuronal atrophy and glial loss have also been reported in postmortem studies of depressive subjects and rodent chronic stress models (1016) . Postmortem studies of subjects with depression and studies of rodent chronic stress also report decreased levels of BDNF and VEGF, as well as their receptors, TRKB and FLK1, respectively, in the PFC and hippocampus(91718192021 ; the VEGF level is also decreased in the cerebrospinal fluid of persons who had attempted suicide (22) .

Conversely, preclinical studies reveal that ketamine and other rapid-acting antidepressants act at least in part by producing the opposite effects, increasing BDNF and/or VEGF release and signaling in the PFC and hippocampus (1023242526 . Ketamine blockade of NMDARs located on gamma-aminobutyric acidergic interneurons leads to disinhibition and a rapid and transient glutamate burst that activates postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, resulting in stimulation of calcium ion (Ca 2+ ) influx through voltage-dependent calcium channels that activates BDNF release (10) ; this increases and reverses the synaptic deficits in the PFC caused by chronic stress (67) , and it is required for the antidepressant-like behavioral actions of ketamine (2327) . The actions of conventional antidepressants are also linked to BDNF and VEGF, although these monoaminergic agents increase trophic factor levels only after long-term treatment and increase only expression but not release of BDNF and VEGF (928293031323334 .

We have recently reported that neuronal VEGF-FLK1 signaling in the medial PFC (mPFC) is also required for the neurotrophic and antidepressant-like behavioral actions of ketamine (24) . Since BDNF is reported to stimulate VEGF expression and release in neuroblastoma cells (35) , we hypothesized that VEGF signaling acts downstream of BDNF to produce the neurotrophic and antidepressant-like actions. The current study addresses this hypothesis as well as the interdependence between BDNF and VEGF signaling.

Discussion

The current results demonstrate several important points. First, a single intra-mPFC infusion of BDNF produces rapid and sustained antidepressant-like actions similar to those of ketamine and intra-mPFC VEGF infusion, consistent with our recent findings (2438) . Second, the antidepressant-like actions of BDNF in three different behavioral paradigms require neuronal-derived extracellular VEGF. Third, BDNF-TRKB signaling stimulates VEGF release in primary cortical neurons, consistent with a previous report showing BDNF-induced VEGF release in a neuroblastoma cell line (35) . Fourth, BDNF-induced neurotrophic actions on dendrite complexity require VEGF-FLK1 signaling in primary cortical neurons. Fifth, the results also demonstrate a reciprocal interdependence, showing that the antidepressant-like and neurotrophic actions of VEGF require BDNF and that VEGF stimulates BDNF release in primary cortical neurons. These results provide the first evidence of a crucial role for interplay between BDNF and VEGF signaling in the neurotrophic and rapid and/or sustained antidepressant-like responses of these factors. Because these studies were conducted in male mice, further studies are needed to determine whether similar effects are observed in female mice.

Previous studies showed that the rapid antidepressant-like actions of ketamine are blocked by the infusion of a BDNF nAb into the mPFC (23) and are blocked in mice with a knockin of the BDNF Val66Met polymorphism (valine at position 66 replaced by methionine), which blocks activity-dependent BDNF release (27) . The behavioral actions of two other rapid-acting antidepressants, rapastinel (an NMDAR modulator) and scopolamine (a nonselective muscarinic acetylcholine receptor antagonist), are also blocked by intra-mPFC infusion of a BDNF nAb and are blocked in Val66Met knockin mice (3846) . These effects differ from those of typical monoaminergic antidepressants, which increase the expression but not the release of BDNF, and they indicate that BDNF release accounts for the rapid actions of ketamine and other rapid-acting agents (910) . In addition, we have recently demonstrated that VEGF release in the mPFC is also required for the rapid antidepressant-like actions of ketamine (24) .

The results of the current study demonstrate that infusion of a VEGF nAb into the mPFC is sufficient to block the antidepressant-like effects of BDNF. The dependence on VEGF was observed in three different antidepressant behavioral paradigms, including models of behavioral despair (FST), motivation and reward (FUST), and anxiety (NSF). While future studies will be needed to test this BDNF–VEGF interaction in chronic stress models, such as chronic unpredictable stress or social defeat (747) , the current results indicate a broad effect across these different behavioral paradigms. Together, the results demonstrate that the antidepressant-like behavioral actions of BDNF are dependent on release of VEGF from excitatory neurons in the mPFC. The results of immunoblot analysis demonstrate that the VEGF nAb does not cross-react with recombinant BDNF, but further studies are needed to demonstrate the lack of cross-reactivity under physiological conditions. In any case, the results of the nAb approach were confirmed with an independent approach, neuronal deletion of VEGF ( CaMKIIα-Crerecombinase line crossed with a Vegfa flox/flox ) (24) . Here we show that the antidepressant-like behavioral actions of BDNF in all three behavioral paradigms are also blocked in the neuronal VEGF–deletion mutants. Since VEGF is expressed by multiple cell types, including neurons, astrocytes, and endothelial cells (33) , we cannot rule out the possibility that VEGF derived from one or more of the other cell types contributes to the BDNF response. However, the results indicate an essential role for VEGF derived from neurons.

Analysis of VEGF release in vivo is technically difficult, so we utilized a primary cortical neuron cell culture system to demonstrate that ketamine stimulates BDNF release (2334) . Here we show that incubation with BDNF increases the release of VEGF in primary cortical neurons, and that coincubation with a selective TRKB inhibitor blocks both BDNF-induced and basal VEGF release. The mechanisms underlying BDNF-TRKB–stimulated VEGF release are unclear, but they could involve effects on neuronal activity or signaling pathways linked with neurotrophic factor release. Evidence for an activity-dependent mechanism is provided by previous studies reporting that infusion of BDNF into the mPFC (48) or hippocampus induces c-Fos expression (49) . Induction of c-Fos is coupled with neuronal activity, although stimulation of intracellular signaling pathways independent of neuronal activity can also increase this immediate early gene. More direct evidence is provided by electrophysiological studies demonstrating that BDNF potentiates glutamatergic transmission by increasing the probability of presynaptic release in hippocampal primary neurons or slices 50515253 and in visual cortex slices(54) . BDNF stimulates the release of Ca 2+ from intracellular stores via activation of phospholipase Cγ (13) , which could stimulate VEGF release ( Figure 6 ). These findings are consistent with the possibility that BDNF-enhancement of glutamatergic transmission stimulates activity-dependent VEGF release. There is also evidence that BDNF stimulates VEGF expression and release via the mechanistic target of rapamycin complex 1 pathway and induction of hypoxia-inducible factor-1α in a neuroblastoma cell line (35) . These reports raise the possibility that activity-dependent, as well as intracellular, signaling could be involved in VEGF release, and further studies are needed to determine the exact pathways. 

Figure 6

Ketamine rapidly increases the number and function of spine synapses on layer V pyramidal neurons in the mPFC, and these synaptic effects require activity-dependent BDNF and VEGF release (6102427) . Similar to ketamine, rapastinel and scopolamine also increase the number and function of spine synapses in the mPFC (38465556) . All of these rapid-acting antidepressants produce neurotrophic actions in primary cortical neurons, including increased BDNF release and increased dendrite complexity (23243446) . We have also reported that ketamine, as well as VEGF induction of dendrite complexity, is completely blocked by a selective FLK1 inhibitor(24) . The current study demonstrates that BDNF increases dendrite complexity in primary neurons and that these neurotrophic effects are completely blocked by incubation with a selective FLK1 inhibitor. These findings provide further evidence that VEGF is required for the neurotrophic actions of BDNF on dendrite complexity.

The results clearly demonstrate a requirement for VEGF in the antidepressant-like and neurotrophic actions of BDNF, but we also examined reciprocal interactions between these two factors. Somewhat surprisingly, we found that the antidepressant-like and neurotrophic effects of VEGF required BDNF release and TRKB signaling. Using similar experimental approaches, the results show that coinfusion of a BDNF nAb into the mPFC blocks the antidepressant-like behavioral responses of VEGF in the three behavioral paradigms tested. The neutralizing antibody used for these studies was specific to BDNF as there was no cross-reactivity with VEGF examined by immunoblot analysis. We also found that incubation of primary cortical neurons with VEGF stimulates the release of BDNF into the culture media, and that this effect is blocked by a selective FLK1 antagonist. In addition, the results show that VEGF stimulation of dendrite complexity is blocked by incubation with a selective TRKB receptor antagonist. The mechanisms underlying VEGF stimulation of BDNF release are unclear but could also involve activity-dependent effects. VEGF increases presynaptic glutamate release probability, leading to enhanced glutamatergic transmission in primary hippocampal slices (57) , and it also increases excitatory transmission via postsynaptic NMDARs (58) . VEGF also stimulates the release of Ca 2+ from intracellular stores via activation of phospholipase Cγ (11) , which could stimulate BDNF release ( Figure 6 ).

Conclusions

In conclusion, the current results in combination with our recent findings (232427343846) demonstrate a key interdependence between BDNF and VEGF signaling in the mPFC and suggest that this reciprocal dependence plays a crucial role in the neurotrophic and antidepressant-like effects of rapid-acting antidepressants. This is particularly clear for the antidepressant-like actions of ketamine, which are blocked by inhibition of either BDNF or VEGF (232427) . Although the requirement for VEGF in the actions of other agents, notably rapastinel and scopolamine, have not been tested and the role of VEGF in patients with depression remains unclear, the prediction is that there is also a requirement for VEGF. These findings raise several interesting possibilities regarding the consequences of this interdependence. For example, previous studies demonstrate that deletion of either BDNF or VEGF in mice is insufficient to produce depressive behaviors, possibly because of the antidepressant-like and neurotrophic actions of the remaining factor (242728) , and it would be interesting to determine whether dual-deletion mutants display depressive-like behaviors. A related consequence is whether a functional polymorphism of one factor would increase vulnerability but is insufficient alone to produce depression, which appears to be the case for the BDNF Val66Met polymorphism (275960) . In contrast, the antidepressant actions of ketamine and other rapid-acting agents could be attenuated by a functional polymorphism of one factor, as reported for the ketamine response in carriers of the BDNF Met allele (27384661) , although this effect also appears to be race specific (62) . The present results provide new insights on the complex interdependence of these two critical neurotrophic factors that could have important consequences for understanding the pathophysiology and treatment of depression.

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Antidepressant Efficacy of Ketamine in Treatment resistant depression

The VAL66MET polymporphism may predict response to Ketamine and suggest additional therapies to add on to those who do not respond:

Our results suggest that MDD patients with the Val/Val BDNF allele at rs6265 are more likely to exhibit increased antidepressant response to ketamine than Met carriers. Liu and colleagues
(8) alluded to the possibility that the weakened antidepressant response to ketamine infusion typically seen in approximately
30% of patients might be related to the Val66Met polymorphism. Our finding is consistent with their hypothesis that rs6265 genotypes could help separate ketamine responders from nonresponders. They also suggested that it may be possible to administer BDNF-enhancing compounds to Met allele-carrying patients before administering ketamine. Standard antidepressants, electroconvulsive therapy, and brain stimulation techniques such as transcranial magnetic stimulation all increase BDNF levels (11,12); exercise also has BDNF secretion-enhancing effects (13).
In contrast, a previous report that included the large STAR*D cohort found no association between traditional antidepressants and rs6265 (14). This suggests that the Val66Met variant
may play a different role in patients treated with traditional antidepressants as opposed to those treated with rapid-acting antidepressants such as ketamine.

Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene,
a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with
alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We
generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in
humans with the variant allele. BDNFMet was expressed in brain at normal levels, but its secretion
from neurons was defective. When placed in stressful settings, BDNFMet/Met mice exhibited increased
anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant
BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.Human Biomarkers of Rapid Antidepressant EffectsMood disorders such as major depressive disorder and bipolar disorder—and their consequent effects on the individual and
society—are among the most disabling and costly of all medical illnesses. Although a number of antidepressant treatments are available
in clinical practice, many patients still undergo multiple and lengthy medication trials before experiencing relief of symptoms. Therefore
a tremendous need exists to improve current treatment options and to facilitate more rapid, successful treatment in patients suffering
from the deleterious neurobiological effects of ongoing depression. Toward that end, ongoing research is exploring the identification of
biomarkers that might be involved in prevention, diagnosis, treatment response, severity, or prognosis of depression. Biomarkers
evaluating treatment response will be the focus of this review, given the importance of providing relief to patients in a more expedient
and systematic manner. A novel approach to developing such biomarkers of response would incorporate interventions with a rapid
onset of action—such as sleep deprivation or intravenous drugs (e.g., ketamine or scopolamine). This alternative translational model for
new treatments in psychiatry would facilitate shorter studies, improve feasibility, and increase higher compound throughput testing for
these devastating disorders.________________________________________________________________________Predictors of Response to Ketamine in Treatment Resistant Depression and Bipolar DisorderAbstract: Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects
in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD)
and bipolar disorder (BD). The identification of depressed sub-populations that are more likely
to benefit from ketamine treatment remains a priority. In keeping with this view, the present
narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as
part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov,
and Scopus were searched for relevant articles from inception to January 2018. The search term
ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder,
predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of
response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family
history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels),
polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate
ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF
allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of
alcohol use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression
more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding,
metabolic-inflammatory alterations are emerging as possible pretreatment response predictors
of depressive symptom improvement, most notably being cognitive impairment. Sophisticated
data-driven computational methods that are iterative and agnostic are more likely to provide
actionable baseline pretreatment predictive information.In addition to pretreatment pro-inflammatory cytokines potentially moderating response to
ketamine, preliminary evidence indicates that circulating vitamin B12 levels may affect the treatment
outcomes with ketamine [34]. Previous reports indicate that higher levels of circulating vitamin B12
are associated with a greater probability of response to conventional antidepressants [35].To contextualize the foregoing results, a single small study with 20 subjects identified vitamin
B12 levels were cross-sectionally associated with bipolar depression. Specifically, ketamine treatment
“responders” had higher levels of circulating vitamin B12 when compared to “non-responders”,
where “responders” were subjects with a 50% or greater reduction of HDRS, as compared to baseline,
on the seventh day after infusion. This result is consistent with studies showing that higher levels of
vitamin B12 are positively correlated with the conventional antidepressant response [21,35].3.5. Neurochemistry Variables
Abnormalities in amino acid neurotransmitter systems are postulated to play a critical role in the
pathoetiology of MDD [38]. Stress-induced depression and cognitive impairment have been found
to be associated with the reduced expression of the gamma-aminobutyric acid (GABA) receptors in
the brain [39].
Using proton magnetic resonance spectroscopy (1H-MRS), Salvadore et al. (2012) measured levels
of the amino acid neurotransmitters gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate
(a surrogate marker of glutamine), in the ventromedial and the dorsomedial/dorsal anterolateral
prefrontal cortex before and after IV ketamine treatment in subjects with MDD (n = 14). Following
ketamine infusion, depressive symptoms significantly improved after 230 min, as assessed by the
changes in the mean MADRS score. The authors reported that while pretreatment GABA and glutamate
did not correlate with an improvement of depressive symptoms, pretreatment Glx/glutamate
ratio was found to be significantly and inversely correlated with the symptomatic improvement
with ketamine [23].

Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusionSymptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion

Highlights


  • Some subjects display antidepressant response to ketamine two weeks post-infusion.

  • Two-week post-infusion data from multiple ketamine trials (MDD & BD) were combined.

  • Smoking history & family history of alcohol use were linked to response at two weeks.

  • Less sadness, anhedonia & trouble concentrating at day 1 predicted greater response.

  • Sleep quality was not significantly improved in responders at two weeks.
  • ________________________________________________________________________________________

rs6265 – Val66Met – the Ketamine SNP   < LINK

rs6265, also known as Val66Met, is a SNP in brain-derived neurotrophic factor BDNF gene. The more common G allele encodes the Val, while the A allele encodes Met.

The A allele may also be protective against depression when subjected to repeated defeat [PMID 17956738g2b2mh blog

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On a driving-based motor learning task subjects with this genotype showed greater error during short-term learning and poorer retention over 4 days, relative to subjects without the polymorphism. The presence of this BDNF polymorphism is associated with differences in brain motor system function, altered short-term plasticity, and greater error in short-term motor learning. [PMID 19745020]

A 2017 study of 1,000 Alzheimer’s disease patients, a third of whom were rs6265(A) carriers, concluded that over the ~7 year study such carriers lost memory and thinking skills somewhat more rapidly than non-carriers.10.​1212/​WNL.​0000000000003980

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Of interest regarding this SNP:

DON’T TELL GEICO: YOU MAY BE A NATURAL BORN BAD DRIVER

Next time you get cut off by a another driver, consider giving the offender a break: One-third of Americans might be genetically predisposed to crappy driving.

No, really, it’s not just your imagination.

In a new study of college undergraduates, those with a common genetic variation scored 20 percent worse in a driving simulator than their counterparts.

“The people who had this genetic variation performed more poorly from the get-go and learned more slowly as they went along,” said Steven Cramer, a University of California, Irvine neurologist, who works on helping stroke victims recover. “Then, when we brought them back four days later, they had more forgetting.”

The single nucleotide polymorphism, or SNP, is just one of millions of single-letter variations between humans’ genetic codes. This one occurs in a gene that produces a protein called brain-derived neurotrophic factor, which helps regulate the formation of new synapses, and the maintenance of old ones. BDNF plays a very important role in what’s called neuroplasticity, or the brain’s ability to rewire itself on the fly.

As described in a paper published in the journal Cerebral Cortex, study participants were asked to drive 16 laps in a driving simulator that was essentially a screen with a steering wheel. As they drove around the course, they attempted to keep their cars on a black strip in the center of the road. The software grades their ability to complete that task quantitatively. And, of a small sample of 29 students, people with that single genetic difference, called Val66Met, performed more poorly than their demographically similar counterparts.

“It’s a very nice study, well designed, and the questions they ask are good,” said Clifford Nass, a co-founder of Stanford’s CarLab, an interdisciplinary research institute. He was not part of the study.

Cramer considers the simulation a good proxy not just for driving, but for other complex motor skills tasks. Because it’s not controlling a motor vehicle, per se, that he’s interested in, but how the brain learns, or relearns complex tasks.

When people have a stroke, and a portion of their brain dies, they have to relearn tasks using different parts of their brains. Individual genes are only part of the symphony of influences that determine individual behavior, but the Val66Met variation appears to have an unusually strong influence on the brain’s activity.

“There is mounting evidence that the one in three people who have this variation have less plasticity than the two-thirds of people who lack that genetic variation,” Cramer said.

Results from a separate study reported earlier this year in Scientific American also found that genetic variation in BDNF helped determined people’s skill at a simple computer game.

The effect is so pronounced, in fact, that Cramer said he could imagine future stroke patient routing within hospitals based on the SNP.

“I wonder if there aren’t going to be treatments, when they have traumatic brain injury and you’re in the rehab ward, where they test the gene and say, ‘Send them to the BDNF ward,'” he said.

So, if the presence of the gene makes you a worse driver, a slower stroke-victim recoverer and possibly has other negative effects, why is the variant still present?

“Variations can stick around just for the fact that they are not that bad for you,” said Bruce Teter, a geneticist who studies the brain at UCLA. “They don’t kill you before you reproduce, in which case, there is no selective advantage or disadvantage.”

But it also turns out that people with the Val66Met variant could be less susceptible to degenerative neurological disorders like Parkinson’s and Huntington’s.

“Originally people thought plasticity had to be good, as it’s related to the ability of the brain to adapt and learn and things like that,” Teter said. “But neuroplasticity can also be bad for you in situations where the kinds of changes that are seen are deleterious.”

But if you want to stay out of car accidents, it’s better to have the dominant BDNF variant, Cramer’s study suggests. And if further work continues to support that idea, the question is, can or should we do anything with that information?

“Let’s pretend that the one in three people are more prone to car accidents,” Cramer said. “It’s up to society to say, how do we deal with that fact?”

SNPwatch: The Bad Driving Gene?

New research suggests that your skills behind the wheel may be affected by your genes.

To better understand the effects of a variant in the BDNF gene on motor skills learning, Steven Cramer and colleagues at UC Irvine tested 29 subjects in a driving simulator. Their results, published in the journal Cerebral Cortex, might make you think twice about whom you go on your next road trip with.

Subjects sat in front of a screen with their hands firmly planted at “10 and 2” on a steering wheel and guided their “car” around a track, attempting to stay centered over a black line. The steering was tuned so that subjects had to begin turning before the screen actually changed.

Over the course of 15 trials, all of the study subjects got better at the driving task. But the seven people who had a T improved less than those with two Cs. When subjects returned to the lab four days later for a final lap, everyone had forgotten how to drive the simulator a little bit, but those with a T did worse.

“These people [with a T at ] make more errors from the get-go, and they forget more of what they learned after time away,” Cramer said in a press release.

The BDNF protein helps to regulate how nerve cells make new connections and maintain old ones. The T version of the variant, also known as the Val66Met, reduces the amount of BDNF available in the brain and has been linked to impaired learning and memory. Studies have shown that stroke victims with this variant don’t recover as well as those who lack it.

But there may be an upside: the variant seems to have a beneficial effect on cognition in people with Parkinson’s disease, Huntington’s disease, lupus and multiple sclerosis.

“It’s as if nature is trying to determine the best approach,” Cramer said. “If you want to learn a new skill or have had a stroke and need to regenerate brain cells, there’s evidence that having the variant is not good. But if you’ve got a disease that affects cognitive function, there’s evidence it can act in your favor. The variant brings a different balance between flexibility and stability.”

Can nurture save you from your own genes? Genes, environment and depression

Welcome to Mind Matterswhere top researchers in neuroscience, psychology, and psychiatry explain and discuss the findings and theories driving their fields. Readers can join them. We hope you will. This week: Genes, Environment, and Depression:How Nurture Can Save You from Your Own Genes _____________________ Introductionby David DobbsEditor, Mind MattersAmong biology’s more riveting inquiries is the investigation of gene-environment interactions — the demonstration that a person’s genes constantly react to experience in a way that changes behavior, which in turn shapes environment, which in turn alters gene expression and so on. As David Olds described a few weeks ago, this new subdiscipline is yielding startling insights about how nature and nurture mix to help determine one’s health and character. This week reviewer Charles Glatt reviews a study that takes this investigation a level deeper, examining how two different gene variants show their power — or not — depending on whether a child is abused, nurtured, or both. As Glatt describes, this study, despite its grim subject, suggests promising things about the power of nurture to magnify nature’s gifts or lift its burdens. _____________________ Gene-Environment Interactions:When Nurture Wears a White Hat Charles GlattWeill Cornell Medical College, New York, NY For centuries, philosophers, theologians and biologists have debated the relative roles of inborn traits versus environmentally defined experiences in determining what and who we are. This nature-nurture debate carries fundamental implications for our understanding of self-determination, or free will. Indeed, as research has begun to identify genetic risk factors for certain behavioral traits, these risk factors have already been used in court (see here and here)to argue that punishment should be lessened for convicted felons — the presumption being that their genes made them inherently more likely to misbehave.The importance and challenge of the nature-nurture debate in behavior has recently spawned a new area of research that looks at the interaction between genetic risk factors and experience in the development of psychopathology. A study led by Joan Kaufman and Joel Gelernter, both of Yale, and published in Biological Psychiatry, has demonstrated what many of us have intuitively concluded, which is that both nature and nurture contribute to who we are. In this particular study, genetic and environmental factors interact to determine risk for depression. In their study, “Brain-Derived Neurotrophic Factor-5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children,” Kaufman, Gelernter and colleagues found distinct gene-environment interactions in the risk for depressive symptoms. Other studies have found similar interactions, but looked mainly at interactions between single genetic and single environmental risk factors. This study ups the ante by examining various interactions among two genetic and two environmental factors, including a four-way interaction with two genetic and two environmental variables. Where the Money Is Kaufman and colleagues took the approach of bank robber Willie Sutton who, when asked why he robbed banks, is said to have replied, “Because that’s where the money is.” Kaufman and colleagues focused on the most well known and accepted genetic and environmental risk factors for depression to see how they interacted with one another to alter risk. On the nature side, they focused on polymorphisms — genetic differences between individuals — that have been implicated in depression through a variety of methods. The first polymorphism is in the regulatory region of the gene for the serotonin transporter. This polymorphism is the 5-HTTLPR, which stands for the serotonin (5-hydroxytryptamine, 5-HT) transporter linked polymorphism. The 5-HTTLPR has received much research attention because it appears to alter the expression of the serotonin transporter molecule, which is the target of the commonly prescribed serotonin-selective reuptake inhibitor (SSRI) class of antidepressants and is itself implicated in depression. Caspi and Moffit and other research groups have repeatedly found this polymorphism to be associated with depression in the presence of stressful life events. The second polymorphism Kaufman studied is the gene for brain-derived neurotrophic factor, or BDNF. BDNF is a molecule that seems to encourage the growth of new neurons; it appears to be central to brain growth and learning. This polymorphism in the BNDF gene alters the efficiency of secretion of this molecule. Recent studies in animals and humans have shown that BDNF levels are decreased during stress and depression and that SSRIs act at least in part by normalizing the levels of BDNF. (BNDF levels have been shown to rise in response to successful SSRI treatment, as well as in response to successful psychotherapy and, for that matter, exercise. An earlier Mind Matters by Francis Lee and Larry Tecott reviewed a rare paper finding a downside to BNDF. ) Thus it is not hard to imagine that polymorphisms (that is, certain variants) of the BDNF gene might interact with other factors to contribute to depression risk. BNDF and 5-HTTLPR, then, were the “nature” factors Kaufman and colleagues examined. From the “nurture,” or environment/experience, side they added two epidemiologically established modifiers of risk for depression — childhood abuse/maltreatment on one hand and, on the other, positive social support.Please Interact Amongst Yourselves The researchers studied 109 children who had been removed from their parents’ care due to reports of abuse or neglect and 87 control children with no reports of abuse or maltreatment. They scored all the children for depressive symptoms such as irritability, crying and reluctance to see friends. High scores on this scale indicate greater depression. They then compared the distribution of these scores in children with different combinations of the 5-HTTLPR and BDNF polymorphisms described above. They found that children with the “bad” form of 5-HTTLPR had higher depressive symptom scores — but only if they had a history of maltreatment. Bad 5-HTTLPR made it more likely (but not certain) that an abused child would develop depression. But it created no effect on depression scores in children without a history of maltreatment. It was like a seed that had to be watered by abuse. This replicates similar findings in studies by Caspi and Moffit and other groups. Kaufman and colleagues then looked at how the different forms of BDNF might affect this picture. They found that a certain version (or allele) of the BDNF gene amplified the effects of the 5-HTTLPR gene, making it even more likely that a given child would develop depression — but again, only if the child had suffered abuse. Finally, Kaufman and colleagues looked at the effects of social support. They asked the children about people in their lives whom they could talk to about personal things, count on to buy them things they needed and other, similar signs of supportive relationships, and from the answers derived a social support score. Children were then characterized as having high or low support. The researchers found that high levels of such nurturing counteracted the effects of the genetic risk factors almost completely.Balance of Power As with any behavioral genetic study, one must be careful not to overinterpret these findings, because virtually no study in behavioral genetics is consistently or completely replicated. Nonetheless, some additional points about this paper can help inform us on the nature-nurture debate. First, depression scores and categorical diagnoses of depression were significantly higher in children with a history of maltreatment versus controls even before any genetic analysis was factored in. In a similar vein, the highest average depression score of any genotype category in the unabused control children was lower than the average depression score for any genotype category in the maltreated children; genes alone weren’t likely to make the child depressed, but maltreatment alone could. These findings suggest that, at least regarding these specific polymorphisms, nurture beats nature. This conclusion will come as a relief to believers in human free will. It also argues strongly for the identification of children at risk for maltreatment and strong actions to reverse the negative effects of this experience.

Oral Scopolamine Augmentation in Moderate to Severe Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Study

Objective:To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram.

Method:In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18–55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n=20) or placebo (n=20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥50% decrease in HDRS score; remission, as HDRS score ≤7.

Results: Augmentation with scopolamine was significantly more effective than placebo (F1,38=5.831, P=.021). Patients receiving scopolamine showed higher rates of response (65%, 13/20 at week 4) and remission (65%, 13/20 at week 6) than the placebo group (30%, 6/20 and 20%, 4/20, respectively; P=.027, P=.004, respectively). Patients in the scopolamine group showed higher rates of dry mouth, blurred vision, and dizziness than the placebo group.

Conclusions: Oral scopolamine is a safe and effective adjunct for treatment of patients with moderate to severe major depressive disorder.

Exploratory genome-wide association analysis of response to ketamine and a polygenic analysis of response to scopolamine in depression.

Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine a review.

Pulsed Intravenous Administration of Scopolamine Produces Rapid Antidepressant Effects and Modest Side Effects

SNP watch link