Suicide is preventable: How can we help our teens?

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Every October, after school starts—and each May, as it ends—there is a spike in the number of teenagers who go to the Yale New Haven Children’s Hospital (YNHCH) emergency department because they are thinking about attempting suicide. They may or may not have struggled with a mental health issue before. But they often have a story: Bullies are harassing them, their parents are divorcing, the academic pressure is crushing them. For some, it’s gender concerns—they have come out as trans or non-binary, and their peers are shutting them out.

“It’s everything—all the pitfalls of being a teenager,” says Kirsten A. Bechtel, MD, a Yale Medicine specialist in the YNHCH, where she says 1,500 to 1,700 of the 40,000 patients a year come in for care for anxiety, depression, and other mental health and behavioral problems, and about 500 of those have suicidal thinking or behavior. In some cases, there may be no clear reason at all, she says.

Suicide is preventable, but rates of suicide are increasing worldwide, and it is now the second leading cause of death in adolescents and young adults (unintentional motor vehicle accidents are first).

Going to the emergency room may be the smartest thing these teenagers can do, Dr. Bechtel says. YNHCH is a Level 1 pediatric trauma center and provides subspecialty care for vulnerable children. Even a single attempt, not to mention an actual suicide, is a tragedy, she says, and a sign that there is a need for more prevention.

Why are teen suicides increasing?

Experts aren’t sure why there is an escalation in teen suicides, and an increase in mental illnesses, like depression and bipolar disorder, that are linked to suicide. One potential trigger may be what’s called “contagion”—when one suicide seems to prompt a chain reaction of suicides. Controversy has swirled around the Netflix series “13 Reasons Why,” which highlights the story of a girl who killed herself and left behind tapes to explain why. While some argue that the show has stimulated a positive conversation around the topic, a study in the Journal of the American Academy of Child and Adolescent Psychiatry showed a 28.9 percent increase in suicide rates in young people ages 10 to 17 in the month after the show’s release in April 2017. (In July 2019, producers followed advice from medical experts and cut a scene that portrayed the suicide.)

Social media also comes under discussion. “There is tantalizing data as far as the effects of social media, but I don’t think we have a good grip on that association,” says Yann Poncin, MD, a Yale Child Study Center psychiatrist, and medical director of the Children’s Day Hospital and In-Home Intensive Child & Adolescent Psychiatric Service. Dr. Poncin has noticed that many teenagers with depression—especially girls—turn to the online world. “I think the use of social media in a teenager with pre-existing concerns does fuel the fire a bit,” he says.

Although Dr. Bechtel has seen cases where social media has been used to alert friends that a teenager was in trouble, Facebook and Instagram can also drive a vulnerable teen to despair, she says. “The negative feedback teenagers get about what they said, what they wore, and who they are is so intense,” she says.

However, some of the biggest issues teens face are not new at all, Dr. Poncin says. A common one is loss—a romantic breakup, the end of a friendship, a death or divorce in the family—combined with underlying psychiatric disorders such as anxiety, depression, and bipolar disorder, which are also on the rise. Another is bullying: In a 2008 study, Yale researchers reviewed studies from 13 countries and found a connection between bullying and suicide.

How do you know a teenager is in trouble?

One thing experts agree on is that teenagers look at the world differently than adults do. “Psychologically, teenagers tend to have more absolutist views. They see things in starker, more rigid colors, and they see fewer gray areas,” says Eli Lebowitz, Ph.D., the director of the Program for Anxiety Disorders at the Yale Child Study Center. “This view can make a problem seem more daunting and a solution seem less likely, where a more mature person might be more accustomed to realizing that life has a combination of good and bad.”

Dr. Lebowitz tells parents who are worried to look at the teen’s ability to function. “‘Normal’ is ultimately the ability to function in way that is in line with expectations for someone of a similar age,” he says. For a teenager, that means attendance, performance, and the ability to get along with others at school, he explains. It is having a satisfying social life in and out of school, and the ability to participate in a reasonably functioning family life (whether or not it is devoid of conflict). It includes the “ability to eat, sleep, and get through a day feeling OK,” he says.

Jennifer Dwyer, MD, Ph.D., a psychiatrist at the Yale Child Study Center, says parents should pay attention if their teenager is chronically angry, cranky, or irritable, since teen depression may manifest through these behaviors rather than strictly through sadness or crying. But sadness can be a symptom too, she adds. Parents also should take note if teenagers are isolating themselves from friends, in constant conflict with the family or peers, having mood swings, giving away their belongings, or increasing their use of alcohol and drugs, she says.

Should you ask if they are thinking about suicide?

Suicidal ideation—essentially thinking about suicide—is not uncommon; in fact, most teenagers probably have thoughts, even if they don’t try it, Dr. Lebowitz says. But he says that many parents are hesitant to ask their teenager the direct question: Are you thinking about hurting yourself? “Not asking is usually a mistake. You are not likely to cause suicidal behavior if you ask about it,” he says. If the answer is yes, Dr. Lebowitz says the parent can follow up with additional questions:

How often do you think about it?
When do you think about it (all the time or only when you are really angry)?
Do you want to do it?
Do you have a specific plan?

If the teenager answers yes, the parent should seek help, Dr. Lebowitz says. “If the answer to the last two questions is yes, that would show the highest level of risk,” he adds. “Even if the answers to those are no, if a teenager thinks about it often, and not only when they are very angry or frustrated, then seeking help is recommended because it would indicate a high level of distress.”

These questions can also help diffuse the situation, Dr. Lebowitz says. “If you are alone thinking about suicide and you’re not able to talk about it, and nobody is asking you, that puts you at higher risk. If someone asks, even if you don’t like that person, it can reduce that sense of isolation. It’s just a fact in the life of a teenager that when somebody does care, it will reduce the risk,” he says.

Getting treatment to prevent suicide

Treatment for suicidal ideation starts with understanding the underlying concerns. Individual therapy, medication management, and the combination of the two could be appropriate, depending on the circumstances. Medicines that treat depression can often include a selective serotonin reuptake inhibitor (SSRI) such as Prozac or Zoloft. The medication can be combined with cognitive behavioral therapy (CBT), which involves regular meetings with a therapist to explore thoughts, feelings, and behaviors to better manage problems. “You can teach someone to recognize their own thinking patterns,” Dr. Lebowitz says. “It’s not instantaneous. But you can train the brain to recognize that pattern and say, “Oh, I’m falling into my thinking trap.””

“A lot of times the relationship with the therapist you are seeing is a good predictor of how therapy might work,” says Dr. Dwyer. “It should be someone the child and the parents feel comfortable bringing their concerns to, and who the child can stick with even when discussing difficult topics.”

Still, about 40 percent of teenagers fail to respond to medication, and half of that 40 percent don’t respond even when they switch to another medication and add psychotherapy, says Dr. Dwyer. “There aren’t a lot of great guidelines or algorithms after you’ve not had success with two medication trials and a trial of evidence-based psychotherapy,” she says.

Given the seriousness of adolescent treatment-resistant depression and suicide, novel treatments are currently being investigated. Ketamine is an anesthetic that has made headlines for its surprising antidepressant effects in adults. Esketamine, a related compound that is delivered as a nasal spray, was approved by the Food and Drug Administration (FDA) this year for treatment-resistant depression in adults. This medication works rapidly, within 24 hours, to reduce depressive symptoms compared to SSRIs, which take weeks to work. Ketamine is also associated with a reduction in suicidality in adults, even after controlling for any improvements in depressive symptoms.

Ketamine and esketamine are only now beginning to undergo rigorous testing for adolescents with treatment-resistant depression and suicidality. A small randomized clinical trial at Yale showed a positive effect of a single ketamine infusion in adolescents with treatment-resistant depression compared to a placebo, but this study only looked at short-term (two-week) outcomes.

Unfortunately, single doses of ketamine typically do not lead to sustained antidepressant responses, and Dr. Dwyer’s group is now conducting a trial looking at a limited number of repeated ketamine doses (which are associated with prolonged antidepressant effects in adults) in this population. But caution is warranted, Dr. Dwyer says, noting that some animal studies suggest that younger ages may be more susceptible to damage to the brain from a high dose of ketamine. It’s important to realize that ketamine is still considered an experimental treatment at this time for pediatric patients, she emphasizes. “I’m hopeful, but I’m also cautious about it, because I think the issues of effective and safe dosing paradigms in the population still need to be worked out,” says Dr. Dwyer.

What we are learning about the teenage brain

Meanwhile, neuroscientists are looking for clues in the brain which, in teens, is still developing. “Adolescence is a time when suicidal thoughts and behaviors can start to emerge,” says psychiatrist and neuroscientist Hilary Blumberg, MD, director of the Mood Disorders Research Program at Yale School of Medicine. She is using magnetic resonance imaging (MRI) to take pictures of the brains of adolescents and young adults with bipolar disorder who are at especially high risk—an estimated 50 percent of whom will attempt suicide at some point.

“We’re identifying the brain circuitry that underlies suicide thoughts and behaviors, how its trajectory of development differs in adolescents at risk for suicide, and how this can be helped,” says Dr. Blumberg, who has seen subtle variations in the prefrontal cortex of young people who have attempted suicide. (The prefrontal cortex has such executive functions as regulating emotions and impulses, and decision-making and planning. It can be compromised by various kinds of child abuse, substance abuse, and other stressors.) She and her research team have also observed subtle differences in the prefrontal structure in teens who go on to make a suicide attempt. “This provides us with new leads about how to generate targeted interventions to prevent suicide.”

Dr. Blumberg is also studying Social Rhythm Therapy (SRT), an approach that she says is showing early promise for normalizing brain circuitry and preventing suicide. SRT is designed to improve mood by regulating emotions and regularizing daily “rhythms”—an example of the latter is sleep patterns. “In order to help people have more regular sleep, you have to look at potential issues that may be causing the disruption. Their issues could be tied to social interactions and activity throughout the day, and a therapist can help them problem-solve around that,” Dr. Blumberg says. “We are encouraged by preliminary results where, after 12 weeks of regularizing daily rhythms, we see reductions in symptoms and suicide risk, and improvements in related brain circuitry.”

“The field has made important progress, but more research is needed,” Dr. Blumberg says. She is the U.S. lead of an international research consortium studying the brain scans of thousands of young people around the world who have suicidal thoughts and behaviors. She notes that the research is promising and may also turn out to be helpful to people who have bipolar disorder, as well as depression and other mental illnesses. “The future is very hopeful. We already have some strategies to prevent suicide, and it is especially hopeful that researchers from different disciplines are coming together in global efforts to discover new ways to reduce suicide.”

What if you are worried about suicide now?

Of course, many families need help immediately. If this is the case, Maryellen Flaherty-Hewitt, MD, a Yale Medicine pediatrician, recommends talking to the family pediatrician. “We routinely ask questions about access to guns, medications in the home, video games teenagers are using, and if they are exposed to violence,” says Dr. Flaherty-Hewitt. The pediatrician should be alert to teenagers who have had no history of mental illness, but who may be having difficulty coping with, say, feelings about sexuality, bullying at school or online, or the transition from one school to another, she says.

“When you have a child who has suicidal ideation, it’s a crisis, and pediatricians want to be part of this conversation. We want to make sure we bring the right people into the mix right away,” Dr. Flaherty-Hewitt says.

If the crisis warrants going to the emergency room, one of the first things that will happen is a counselor will sit with the teenager and listen to their concerns. In some cases, the patient will be admitted to the hospital or referred to YNHCH’s Partial Hospitalization Program. But, Dr. Bechtel says, “I’m always amazed how some of these kids are alright. Maybe they needed some respite, or maybe the biggest problem is that their behavioral health needs aren’t being met in the community,” she says.

For most young patients, thoughts of suicide are manageable, specialists say. “It may be a lifelong vulnerability, but there are many people who used to have an anxiety disorder or depression,” says Dr. Lebowitz. “We need to foster a belief in treatment and the understanding that having these problems can be part of life.”

Social Rhythm Therapy (SRT)

Social-Rhythm-Therapies-for-Mood-Disorders-an-Update Download

Magic Medicine?

Patients are turning to ketamine and other psychoactive drugs for mental health treatment

Sarah Jones, a 42-year-old stay-at-home mom in Woodstock, has struggled with depression since childhood. She’s tried multiple antidepressants and therapies over the years, and last fall, her medications once again quit working. Then Jones heard a radio ad about a new approach for depression — a drug called ketamine.

Ketamine is an anesthetic commonly used by veterinarians. It’s also used illegally as a club drug for its mind-altering, euphoric effects. And recently, it’s been touted for a new use: treating depression.

Other psychoactive drugs like Ecstasy, LSD and magic mushrooms are also being considered as treatments for mental illnesses. Some of the drugs are under consideration for approval by the Food and Drug Administration (FDA).

Ketamine goes mainstream

Over the past several years, ketamine clinics, which deliver the drug to patients through intravenous (IV) infusions, have sprung up in Chicago and around the country to treat depression and other mental health conditions, including post-traumatic stress disorder (PTSD) and anxiety.

Using the drug this way is considered an off-label use, meaning it’s used in a manner different from what’s been specified by the FDA. IV ketamine treatments for depression are not approved by the FDA and are often pricey. They are typically not covered by insurance.

In March 2019, the FDA approved a nasal-spray version of ketamine, called esketamine (marketed as Spravato), to help the estimated 5 million Americans whose depression hasn’t responded to other treatments. Research shows that ketamine can more rapidly turn around depression than traditional antidepressants. Suicidal patients can find their urge to harm themselves quelled within 24 hours, rather than the weeks or months it takes a drug like Prozac to take effect, researchers have found.

It’s a bold move by the FDA to approve a completely new class of antidepressants and to open up a new realm of drugs that are considered psychedelics and psychoactive to be used as a medical treatment for something as common as depression,” says Bal Nandra, MD, an anesthesiologist and founder of IV Solution, which for almost three years has provided IV ketamine in downtown Chicago.

Nandra hasn’t decided whether to offer the recently FDA-approved esketamine nasal spray in addition to IV ketamine. “It’s not nearly as effective or rapid acting as IV ketamine,” he says.

Lifting depression

Jones received IV infusions of ketamine at Nandra’s South Dearborn Street clinic in November 2018. She followed Nandra’s typical regimen of six treatments given over a period of about two weeks, at a price of $500 to $600 per infusion.

During these sessions, patients are seated in a private room, where they are hooked up to an IV for about 45 minutes, usually reclining on a medical lounge chair with the room darkened. Often, they wear an eye mask and listen to music. Patients are monitored by nurses or other staff for side effects, and those who become anxious may receive some sedation. After the infusion is over, patients are observed for about 30 to 45 minutes before being released.

Ketamine can cause patients to feel dissociated from their bodies. The experience left Jones with a sense of the vastness of the universe and the idea that “there is something more out there than what we experience in our everyday life,” she says. “It almost takes you away from your suffering.”

Most patients feel better after the first few ketamine infusions, Nandra says, though some take longer. Jones felt her depression lifting after her first treatment.

It’s a bold move by the FDA … to open up a new realm of drugs that are considered psychedelics and psychoactive to be used as a medical treatment for something as common as depression.”

Jones returns to IV Solution every two months for one-session booster infusions to keep her depression at bay.

She has been able to dramatically reduce her antidepressant use, while continuing in therapy.

“Ketamine not only restored my brain to being able to function but also gave me insight into some life choices that were adding to my depression,” Jones says. Today, she adds,

“I don’t remember what depression feels like. I’m so happy!”

Gregory Teas, MD, a psychiatrist with the AMITA Health Behavioral Medicine Institute, says the clinic will likely start offering esketamine treatment starting this fall. Esketamine has a wholesale cost of $590 to $885 per dose, but the treatment may be covered by insurance, Teas says. Patients can’t take it at home but must go to a medical facility, where it is given under strict protocols, including two hours of monitoring afterward.

Like other experts, Teas cautions that long-term studies on the use of ketamine and esketamine are needed. While the drug primarily works on receptors in the brain’s glutamate system, it also uses opioid and dopamine pathways, he says, which means it could be addictive for some patients.

Exploring other possibilities

Other psychoactive drugs may soon join ketamine as treatments for psychiatric conditions. The University of Chicago’s Human Behavioral Pharmacology Laboratory, directed by Harriet de Wit, PhD, has been studying MDMA (also known as Ecstasy) as a possible treatment.

MDMA, which causes people to feel loving toward themselves and others, may be helpful for people with PTSD and autism-related social anxiety, says researcher Anya Bershad, MD, PhD, who recently left the lab to complete a psychiatry residency at the University of California Los Angeles.

A national phase 3 clinical trial of MDMA used in conjunction with psychotherapy for PTSD is underway, though Chicago is not a study site. If these trials go well, researchers expect the FDA might approve MDMA in 2021 for use with psychotherapy as a treatment for PTSD.

Also being studied at the University of Chicago: microdosing with LSD to treat depression and anxiety. Study participants receive one-tenth or one-twentieth of a recreational dose, usually every three days, Bershad says. They don’t experience mind-altering psychedelic effects, but they do report feeling the “experience of unity,” even at those tiny doses, she says.

Other labs outside Illinois are studying psilocybin, or magic mushrooms, for their potential in treating anxiety, depression and eating disorders. Medical marijuana is also being researched for the treatment of PTSD, though studies differ so far on its effectiveness.

As for ketamine, Nandra says in the years he’s been offering IV ketamine treatments he has seen many patients recover. “For these people, it lasts,” he says. “They do great. Their lives completely change. … It’s pretty amazing.”

Citocholine for Brain Health

Behind the Buzz: How Ketamine Changes the Depressed Patient’s Brain

The anesthetic-cum-party drug restores the ability to make connections among brain cells

The Food and Drug Administration’s approval in March of a depression treatment based on ketamine generated headlines, in part, because the drug represents a completely new approach for dealing with a condition the World Health Organization has labeled the leading cause of disability worldwide. The FDA’s approval marks the first genuinely new type of psychiatric drug—for any condition—to be brought to market in more than 30 years.

Although better known as a party drug, the anesthetic ketamine has spurred excitement in psychiatry for almost 20 years, since researchers first showed that it alleviated depression in a matter of hours. The rapid reversal of symptoms contrasted sharply with the existing set of antidepressants, which take weeks to begin working. Subsequent studies have shown ketamine works for patients who have failed to respond to multiple other treatments, and so are deemed “treatment-resistant.”

Despite this excitement, researchers still don’t know exactly how ketamine exerts its effects. A leading theory proposes that it stimulates regrowth of synapses (connections between neurons), effectively rewiring the brain. Researchers have seen these effects in animals’ brains, but the exact details and timing are elusive.

A new study, from a team led by neuroscientist and psychiatrist Conor Liston at Weill Cornell Medicine, has confirmed that synapse growth is involved, but not in the way many researchers were expecting. Using cutting-edge technology to visualize and manipulate the brains of stressed mice, the study reveals how ketamine first induces changes in brain circuit function, improving “depressed” mice’s behavior within three hours, and only later stimulating regrowth of synapses.

As well as shedding new light on the biology underlying depression, the work suggests new avenues for exploring how to sustain antidepressant effects over the long term. “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine,” says Carlos Zarate, chief of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health, who was not involved in the study. “This work will likely set a path for what treatments should be doing before we move them into the clinic.”

Another reason ketamine has researchers excited is that it works differently than existing antidepressants. Rather than affecting one of the “monoamine” neurotransmitters (serotonin, norepinephrine and dopamine), as standard antidepressants do, it acts on glutamate, the most common chemical messenger in the brain. Glutamate plays an important role in the changes synapses undergo in response to experiences that underlie learning and memory. That is why researchers suspected such “neuroplasticity” would lie at the heart of ketamine’s antidepressant effects.

Ketamine’s main drawback is its side effects, which include out-of-body experiences, addiction and bladder problems. It is also not a “cure.” The majority of recipients who have severe, difficult-to-treat depression will ultimately relapse. A course of multiple doses typically wears off within a few weeks to months. Little is known about the biology underlying depressive states, remission and relapse. “A big question in the field concerns the mechanisms that mediate transitions between depression states over time,” Liston says. “We were trying to get a better handle on that in the hopes we might be able to figure out better ways of preventing depression and sustaining recovery.”

Chronic stress depletes synapses in certain brain regions, notably the medial prefrontal cortex (mPFC), an area implicated in multiple aspects of depression. Mice subjected to stress display depressionlike behaviors, and with antidepressant treatment, they often improve. In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

For the experiment, some mice became stressed when repeatedly restrained, others became so after they were administered the stress hormone corticosterone. “That’s a strength of this study,” says neuroscientist Anna Beyeler, of the University of Bordeaux, France, who was not involved in the work, but wrote an accompanying commentary article in Science. “If you’re able to observe the same effects in two different models, this really strengthens the findings.” The team first observed the effects of subjecting mice to stress for 21 days, confirming that this resulted in lost spines. The losses were not random, but clustered on certain dendrite branches, suggesting the damage targets specific brain circuits.

The researchers then looked a day after administering ketamine and found that the number of spines increased. Just over half appeared in the same location as spines that were previously lost, suggesting a partial reversal of stress-induced damage. Depressionlike behaviors caused by the stress also improved. The team measured brain circuit function in the mPFC, also impaired by stress, by calculating the degree to which activity in cells was coordinated, a measure researchers term “functional connectivity.” This too improved with ketamine.

When the team looked closely at the timing of all this, they found that improvements in behavior and circuit function both occurred within three hours, but new spines were not seen until 12 to 24 hours after treatment. This suggests that the formation of new synapses is a consequence, rather than cause, of improved circuit function. Yet they also saw that mice who regrew more spines after treatment performed better two to seven days later. “These findings suggest that increased ensemble activity contributes to the rapid effects of ketamine, while increased spine formation contributes to the sustained antidepressant actions of ketamine,” says neuroscientist Ronald Duman, of the Yale School of Medicine, who was not involved in the study. Although the molecular details of what happens in the first hours are not yet fully understood, it seems a restoration of coordinated circuit activity occurs first; this is then entrenched by neuroplasticity effects in synapses, which then maintain behavioral benefits over time.

To prove that new synapses were a cause of antidepressant effects, rather than just coinciding with the improved behaviors, the team used a newly developed optogenetic technique, which allowed them to eliminate newly formed spines using light. Optogenetics works by introducing viruses that genetically target cells, causing them to produce light-sensitive proteins. In this case, the protein is expressed in newly formed synapses, and exposure to blue light causes the synapse to collapse. The researchers found that eliminating newly formed synapses in ketamine-treated mice abolished some of the drug’s positive effects, two days after treatment, confirming that new synapses are needed to maintain benefits. “Many mechanisms are surely involved in determining why some people relapse and some don’t,” Liston says, “ but we think our work shows that one of those involves the durability of these new synapses that form.”

And Liston adds: “Our findings open up new avenues for research, suggesting that interventions aimed at enhancing the survival of these new synapses might be useful for extending ketamine’s antidepressant effects.” The implication is that targeting newly formed spines might be useful for maintaining remission after ketamine treatment. “This is a great question and one the field has been considering,” Duman says. “This could include other drugs that target stabilization of spines, or behavioral therapies designed to engage the new synapses and circuits, thereby strengthening them.”

The study used three behavioral tests: one involving exploration, a second a struggle to escape, and a third an assessment of how keen the mice are on a sugar solution. This last test is designed to measure anhedonia—a symptom of depression in which the ability to experience pleasure is lost. This test was unaffected by deleting newly formed spines, suggesting that the formation of new synapses in the mPFC is important for some symptoms, such as apathy, but not others (anhedonia)—and that different aspects of depression involve a variety of brain circuits.

These results could relate to a study published last year that found activity in another brain region, the lateral habenula, is crucially involved in anhedonia, and injecting ketamine directly into this region improves anhedonia-related behavior in mice. “We’re slowly identifying specific regions associated with specific behaviors,” Beyeler says. “The factors leading to depression might be different depending on the individual, so these different models might provide information regarding the causes of depression.”

One caveat is that the study looked at only a single dose, rather than the multiple doses involved in a course of human treatment, Zarate says. After weeks of repeated treatments, might the spines remain, despite a relapse, or might they dwindle, despite the mice still doing well? “Ongoing effects with repeated administration, we don’t know,” Zarate says. “Some of that work will start taking off now, and we’ll learn a lot more.” Of course, the main caution is that stressed mice are quite far from humans with depression. “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans,” Beyeler says.

Default Mode Network and Mood

The Default Mode Network (sometimes called simply the default network or the DMN) refers to an interconnected group of brain structures that are hypothesized to be part of a functional system. The DMN includes areas of the brain which researchers found to have higher activity when the mind was supposed to be at rest. For example, when you are day dreaming, thinking about the future, replaying memories, etc. without a specific goal in mind. Now, why would we care about this? The DMN is found to have increased activity in certain mood and pain disorders. That being said, let’s look at our 3 reasons why you should know about the DMN.

Reason #1: Increased DMN activity and functional connectivity is found in depression [1] as well as in pain disorders [2]. In these disorders, there is much rumination. Rumination is where you have repetitive thoughts. Those who deal with depression may replay depressing or sad memories over and over in their mind. This prevents them from healing and creating room for more positive emotions and memories. Additionally, those with pain may become fixated on the pain itself, or replay the events which lead to them having the pain. This type of circular, overactive thinking occurs in the DMN.

Reason #2: Reducing activity in the DMN can decrease rumination, which in turn can reduce pain and depressed feelings. In experienced meditators, there was decreased activity in the DMN, as well as increased connectivity in the regions of the brain responsible for self-monitoring and cognitive control [3]. Thus, giving us a scientific reason for the benefits of meditation. We all have moments where we have unhelpful replays in our minds, and meditation can help us in breaking and reducing this ruminative behavior.

Reason #3: Ketamine reduces the functional activity in the DMN! A study showed that the connectivity of the DMN along with another portion of the brain, the dorsal nexus, was decreased after ketamine infusions [4]. So ketamine can effectively turn down the overactive areas in our mind, which can lead to an improved mood and less pain.

In conclusion, you are much more than your mind, and before you can transcend something which does not serve you, you must know about it. Now that you know more about the default mode network, how your brain works, and rumination, what action will you take today

References:

NEUROGENESIS

When you break the word itself down, it comes in two parts: “neuro” as in neuron, and “genesis” as in creation. Neurogenesis broadly speaking is the process by which new neurons are created in the brain, thus allowing for increased plasticity of the brain and stronger synaptic connections. Adult neurogenesis is the process by which new neurons are created and integrated into existing brain circuitry when you are an adult. Adult neurogenesis can be seen in the olfactory bulb and the hippocampus.

The hippocampus is an S-shaped structure within the medial part of the temporal lobe and is densely packed with neurons. It a part of the limbic system, which also includes the hypothalamus and the amygdala. This region helps regulate emotion, memory, and arousal. Furthemore, the hippocampus is of particular interest because of its role in learning and motivation.

The monoamine hypothesis of depression states that antidepressants, a.k.a. selective serotonin reuptake inhibitors (SSRIs), work by increasing the levels of serotonin in the brain. It is thought that because SSRIs act on monoamine systems in the brain, which are involved in regulating emotion, therefore antidepressant results will be produced in individuals with depression.

However, treatment using SSRIs often take weeks to months to produce antidepressant effects, and sometimes they’re not even produced at all. People who have difficulty treating their depression with standard medical treatments are described as having treatment-resistant depression (TRD). Researchers are constantly working to find the mechanisms of depression and how it works in the brain.

Published in Neuropsychopharmacology in 2015, Hill and colleagues conducted a study on mice to measure whether inducing adult neurogenesis in the hippocampus positively affects anxious and depressive behaviors. Studies like these are often administered to mice first because they share similar biological and behavioral components to that of humans.

They found that when the mice were treated chronically with corticosterone (stress hormone secreted by the adrenal glands), increasing adult neurogenesis in the hippocampus does reduce anxiety and depression (1).

When we take these findings and circle back to ketamine, it makes sense. One of ketamine’s main mechanisms is increasing neurogenesis and synaptogenesis, allowing for neuroplasticity. Synaptogenesis is the process by which synaptic connections between the neurons in the brain are created. Increasing neuroplasticity allows for the brain to reorganize its connections more efficiently in response to stress and new changes in its environment. Essentially it is what keeps the brain resilient.

So ketamine increases neurogenesis, but why does it have the reputation of being a fast-acting antidepressant, especially for those with TRD? While we don’t have all of the answers to ketamine’s mechanisms, we do know this:

Ketamine Rapidly enhances the Maturation of Neurons

RATHER THAN INCREASING SEROTONIN, KETAMINE ACTS ON THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR AND THE GLUTAMATE NEUROTRANSMITTER

Ketamine increases the production of Brain Derived Neurotrophic Factor

Ketamine reduces the functional activity of the Default Mode Network

Beyond these multiple mechanisms of action, we also believe there is another level beyond the physical. Accordingly, we incorporate the bio-psycho-social-spiritual model of medicine at our clinic to take a holistic view for our patients!

References:

Hill, A. S., Sahay, A., & Hen, R. (2015). Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology, 40(10), 2368–2378. doi: 10.1038/npp.2015.85

Researchers hypothesize that neurogenesis, or neuron growth, is an antidepressant action. This hypothesis is linked to the understanding that nearly all antidepressants increase birth of granule neurons in rodents. Ketamine, however, has such rapid antidepressant effects, suggesting that the mechanisms involved with ketamine are not involved with neuron birth. Instead, researchers hypothesized that ketamine’s rapid effects are due to it enhancing the maturation of neurons born previously.

To test this hypothesis, researchers injected rats with ketamine, assessing the effects of the ketamine on granule neurons. Researchers found that the ketamine rapidly affected the neurons, increasing mature neurons within two hours. A single injection of ketamine increased cell proliferation and functional maturation. For at least four weeks following the injection, depressive symptoms in rats were decreased.

In conclusion, ketamine has rapid, lasting effects on the recruitment of neurons into the hippocampal region of the brain. The hippocampus is believed to play a role in memory, spacial recognition, and avoidance-approach conflict processing. However, new neuron growth was independent of the antidepressant effects of the ketamine. The antidepressant effect may be due to ketamine’s work on neuron growth, but not on new neuron growth.

epression is among the most disabling conditions in our society. According to the World Health Organization, depression is the leading cause of ill health and disability worldwide. In America, 12.5% of individuals over the age of 12 have filled an antidepressant prescription. Yet, the effectiveness of these medications are still lacking. Many patients don’t respond to antidepressant medications, and it can take months for the medicine to kick in. Unfortunately, many patients will regain their depression after being on medications long term.

Over 50 years ago, the hypothesis that low concentrations of serotonin in the central nervous caused depression was proposed. This appealed to many doctors & scientists, because we finally had a potential biological mechanism to explain depression. Accordingly, many antidepressants were developed to increase serotonin to help relieve depression. Although, it can work for some patients many patients do not respond or have significant side effects.

SO WHAT IS A PERSON TO DO IF THEY HAVE TREATMENT-RESISTANT DEPRESSION?

One cutting-edge option is targeting a completely different neurotransmitter – GLUTAMATE. Glutamate is an excitatory neurotransmitter and the most abundant neurotransmitter in the brain and central nervous system. Ketamine works on the glutamate system by blocking it’s activity at the N-Methyl-D-Aspartate (NMDA) receptor.

Ketamine raises brain derived neurotrophic factor (BDNF) levels, thereby enhancing connections between neurons and increasing neuroplasticity. It’s literally changing the brain. In animal studies, the cascade of effects from ketamine created a rapid proliferation of dendritic spines that was associated with less depression. In a functional MRI brain study of humans, ketamine seemed to restore the functional connectivity in those patients with depression.

Interestingly, ketamine is known to affect other receptors beyond the NMDA receptor, and have anti-inflammatory as well as epigenetic effects. Also, the breakdown products of ketamine, like (S)-norketamine and (2R, 6R)-hydroxynorketamine, may also play a role in helping with depression.

Even though we have some understanding of how ketamine works, we still don’t fully comprehend how ketamine is working exactly in patients with depression.

“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.

— John A. Wheeler, Physicist

As we continue to learn more about ketamine and depression, more questions and unknowns will surely develop.

Therefore, it’s critical to expand our understanding of depression beyond the simple serotonin and even glutamate neurotransmitters. The human body, brain, and consciousness is one of the most complex systems we have ever encountered. Although, we may never fully understand the intricacy of it all, we can still take action.

We can be pragmatic and responsibly use ketamine for carefully selected patients. In addition to ketamine infusions, we can encourage psychotherapy, exercise, meditation, prayer, positive community, a good night’s rest, and a healthy diet to help people with depression.

At Reset Ketamine, we utilize the bio-psycho-social-spiritual model that encompasses a whole person approach to health. We believe health is not merely the absence of illness, but a state of physical, social, mental, and spiritual well-being. We believe ketamine can be the catalyst to create paradigm shifts to help patients live a full life.

References:

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778. doi:10.1016/j.neuron.2019.02.005

ccording to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.

Ketamine, possibly the most widely used anesthetic agent in the world, has been shown by numerous studies to have rapid antidepressant effects when used off-label. The full mechanism by which ketamine induces these therapeutic effects is still a mystery. What researchers do understand is that increased levels of brain derived neurotrophic factor (BDNF), a protein that plays a role in the growth and maintenance of neurons, is involved. But how and where does ketamine increase BDNF?

A recent study in 2017 suggests that HDAC5, an enzyme affecting DNA and chromosomes, regulates the antidepressant effects of ketamine through a process called phosphorylation, which regulates protein function. Ketamine influences the transcription (the process by which DNA is turned into RNA) of BDNF and increases BDNF levels in the central nervous system.

Additionally, a study in 2015 demonstrated that the antidepressant effects of ketamine are based on the release of BDNF and the activation of the L-type voltage-dependent calcium channels (VDCC). Researchers found that the release of BDNF regulates the antidepressant effects of ketamine, further clarifying the underlying mechanisms that ketamine utilizes.

Furthermore, researchers observed in another 2015 study that dysfunctional levels of BDNF may be linked to depression, and that ketamine treatment can produce a positive effect within certain pathways of the brain, such as in the prefrontal cortex and nucleus accumbens. In this animal study, rats were divided into four groups: saline+deprived, saline+non-deprived, ketamine+deprived, and ketamine+non-deprived. Ketamine infusions were administered daily for 14 days. Researchers then observed the animals’ brain structures. They observed that the deprived rats had reduced levels of BDNF in the amygdala, hippocampus and nucleus accumbens. The ketamine reversed the levels of BDNF in the amygdala and nucleus accumbens. This is important because the amygdala plays a critical response in fear and strong emotions, while the nucleus accumbens is essential in motivation, aversion, reward, and learning.

In addition to ketamine’s effect on the default mode network, neurons, brain waves, glutamate neurotransmitter, and inflammation, by understanding ketamine’s impact on BDNF, we can gain a deeper insight into the mystery of how our brain works. Ultimately, as Socrates once said, “To know thyself is the beginning of wisdom.”

References:

Choi, Miyeon, et al. “Ketamine Induces Brain-Derived Neurotrophic Factor Expression via Phosphorylation of Histone Deacetylase 5 in Rats.” Biochemical and Biophysical Research Communications, vol. 489, no. 4, 2017, pp. 420–425., doi:10.1016/j.bbrc.2017.05.157.

Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.

Réus, Gislaine, et al. “Ketamine Treatment Partly Reverses Alterations in Brain Derived- Neurotrophic Factor, Oxidative Stress and Energy Metabolism Parameters Induced by an Animal Model of Depression.” Current Neurovascular Research, vol. 12, no. 1, 2015, pp. 73–84., doi:10.2174/1567202612666150122122924.

Depression is among the most disabling conditions in our society. According to the World Health Organization, depression is the leading cause of ill health and disability worldwide. In America, 12.5% of individuals over the age of 12 have filled an antidepressant prescription. Yet, the effectiveness of these medications are still lacking. Many patients don’t respond to antidepressant medications, and it can take months for the medicine to kick in. Unfortunately, many patients will regain their depression after being on medications long term.

SO WHAT IS A PERSON TO DO IF THEY HAVE TREATMENT-RESISTANT DEPRESSION?

Even though we have some understanding of how ketamine works, we still don’t fully comprehend how ketamine is working exactly in patients with depression.

“We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.

— John A. Wheeler, Physicist

As we continue to learn more about ketamine and depression, more questions and unknowns will surely develop.

References:

THETA BRAIN WAVES & THE ANTI-ANXIETY EFFECTS OF KETAMINE

According to a study published in the International Journal of Neuropsychopharmacology in 2018, specific brain waves are related to the anti-anxiety effects of ketamine. The brain waves involved in this function are called theta waves, found in the right frontal area of the brain. Ketamine can treat a wide variety of neurotic disorders, such as depression, generalized anxiety disorder, and PTSD, but researchers do not conclusively understand how ketamine works to relieve the symptoms of these disorders.

To better understand the therapeutic effects of ketamine, researchers studied the brain activity of patients given ketamine. Patients with generalized anxiety disorder and/or social anxiety disorder were administered ketamine and hooked up to a monitor measuring electrical brain activity (EEG). Ketamine affected the power of the brain waves by increasing the fast waves and decreasing the slow waves. However, only a single frequency band was related to therapeutic effects—the theta waves.

Human consciousness is believed to be related to neurons firing synchronously in various frequencies. Theta waves are in the 4 to 7 hertz rhythms. During meditation, theta waves predominated and were most abundant in the frontal and middle parts of the brain. Professor Jim Lagopoulos states, “These types of waves likely originate from a relaxed attention that monitors our inner experiences. Here lies a significant difference between meditation and relaxing without any specific technique. Previous studies have shown that theta waves indicate deep relaxation and occur more frequently in highly experienced meditation practitioners. When we measure mental calm, these regions signal to lower parts of the brain, inducing the physical relaxation response that occurs during meditation.”

So ketamine infusions seems to put the brain into a similar state that highly experienced meditators can achieve allowing for a calm, relaxed state of mind.

In conclusion, the anti-anxiety relief of ketamine may related to a very specific portion of electrical brain activity. This finding combined with the knowledge that ketamine blocks the NMDA glutamate receptor helps researchers understand how ketamine affects the brain. This preliminary study paves the way for future research on brain studies and ketamine.

Ketamines impact on BDNF

According to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.

References:

Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.

Who should not get Ketamine?

Here are the 7 types of people who should NOT take ketamine:

People with uncontrolled high blood pressure (hypertension). Ketamine is known to increase blood pressure, and in the setting of already high blood pressure the increase could get so high as to cause a heart attack or stroke. So it is important to have blood pressure monitored throughout your infusion.
People with unstable heart disease (such as arrhythmias, congestive heart failure, coronary artery disease, etc.). Ketamine can increase heart rate and cardiac output (how hard your heart is working), which could worsen various heart conditions.
People with untreated or uncontrolled thyroid disease (especially hyperthyroidism). In thyroid diseases such as hyperthyroidism, the body may already have an increased heart rate i.e. sympathetic overdrive which could be worsened with taking ketamine.
People with active substance abuse. Ketamine can be used to treat addiction, however, infusions are given once the patient has detoxed or is off of the drugs the individual is addicted to. When a person is taking multiple drugs, the way their body may react may be unpredictable and potentially life threatening.
People in an active manic phase of bipolar disorder. Ketamine can cause an altered mental state. If a person is already in an active manic state, ketamine could potentially worsen or enhance a worrisome emotional state.
People with active delusions and hallucination symptoms (not taking prescription or while on street drugs). Similar to the point made in #5, a person can experience out of body experience or similar non ordinary state experiences when given ketamine. Ketamine could potentially enhance or worsen delusions and active hallucinations.
Lastly, patients who have tried ketamine in the past and have had bad reactions to this medication. If someone has been given ketamine for a procedure and had an adverse effect, we would suggest holding off.

Psychedelic therapy, or at least the talk of them, is very popular as of this writing. Ketamine is currently the only legal and FDA approved psychedelic in the United States. You may have heard about ketamine as a recreational drug or as an animal tranquilizer but not sure what to think about it. You may have depression, anxiety, OCD, or PTSD which is not being helped by standard treatments. You may even know of a loved one who could benefit from ketamine infusions.

There is a lot of information out there. Some good and some not so good information in giving you a straight-forward understanding of ketamine as a treatment option for various mental health disorders. So welcome to our beginner’s guide, where we’ll cover the basics of what you need to know.

WHAT IS KETAMINE?

Ketamine was first synthesized in the 1960’s for use as a general anesthetic and FDA approved in 1970. Ketamine blocks the activity of glutamate (an excitatory neurotransmitter), which binds to and activates the NMDA receptor. This NMDA receptor blockade is known to increase brain derived neurotrophic factor (BDNF).

Increases in BDNF results in increased neurogenesis and neuroplasticity. This helps those with chronic pain and depression to restore their neuronal activity and synaptic strength in the prefrontal cortex, restoring and resetting their brain back to a healthier state.

If you want to further learn how ketamine works check out: The 4 Mechanisms of How Ketamine Works

Ketamine has been traditionally used in the operating room and emergency departments for sedation and pain control. Ketamine has a colorful history and is known to be used in veterinary medicine as a “animal tranquilizer” and even a recreational club drug of abuse. However, ketamine is the most commonly medicine used worldwide for sedation and the World Health Organization (WHO) places ketamine in its List of Essential Medicines.

Ketamine can be delivered into the body in several forms: oral (pill form), intranasal (insufflated into the nose), intramuscular (injected into the muscle), and intravenous (into the vein). Most ketamine clinics provide ketamine in the intravenous form as a slow infusion. There are other clinics that may provide ketamine in the other forms in conjunction with psychotherapy.

WHY DOCTORS ARE USING KETAMINE?

Ketamine is effective in chronic pain, PTSD, depression, and other illnesses. Because of ketamine’s unique properties, many people are experiencing rapid, effective relief compared to traditional treatments, such as selective serotonin reuptake inhibitors (SSRIs) which can take months to take effect.

When individuals are receiving ketamine for these treatments, ketamine is being used “off-label,” meaning that it is not being for the specific indication approved by the United States Food and Drug Administration (FDA). To get FDA approval for an indication, it requires multiple stages of research to evaluate the safety and efficacy for that specific use. In 1970, ketamine was FDA approved for use as the,“sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.” But all other uses are considered “off-label.” Fortunately, once a drug is FDA approved, physicians have the freedom to use their best clinical judgment in prescribing drugs for other purposes than originally intended.

WHO SHOULDN’T GET KETAMINE?

To understand who should not get ketamine, you’ll need to understand the effect of ketamine on the body. Ketamine can increase the heart rate and blood pressure and stress the cardiac function of anyone who has uncontrolled heart problems. Ketamine is used during medical procedures and operations for analgesia (i.e. doctors can perform surgeries and procedures without causing pain to the patients) due to its dissociative property. This dissociative property is also, according to research, associated with better antidepressant effects during ketamine infusions. While this is a wonderful property if a person has a mental disorder that is characterized by hallucinations or delusions, undergoing ketamine infusions could actually worsen these conditions.

RAPID RESOLUTION OF OBSESSIONS AFTER AN INFUSION OF INTRAVENOUS KETAMINE IN A PATIENT WITH TREATMENT-RESISTANT OBSESSIVE-COMPULSIVE DISORDER: A CASE REPORT

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