How New Ketamine Drug Helps with Depression

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An illustration of a woman suffering from depression who might be helped by esketamine

The FDA approval of esketamine gives doctors another valuable tool in their arsenal against depression—and offers new hope for patients no one had been able to help before. “This is a game changer,” says John Krystal, MD, chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the country.

On March 5, the Food and Drug Administration (FDA) approved the first truly new medication for major depression in decades. The drug is a nasal spray called esketamine, derived from ketamine—an anesthetic that has made waves for its surprising antidepressant effect.

Because treatment with esketamine might be so helpful to patients with treatment-resistant depression (meaning standard treatments had not helped them), the FDA expedited the approval process to make it more quickly available. In one study, 70 percent of patients with treatment-resistant depression who were started on an oral antidepressant and intranasal esketamine improved, compared to just over half in the group that did not receive the medication (called the placebo group).

“This is a game changer,” says John Krystal, MD, chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the country. The drug works differently than those used previously, he notes, calling ketamine “the anti-medication” medication. “With most medications, like valium, the anti-anxiety effect you get only lasts when it is in your system. When the valium goes away, you can get rebound anxiety. When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” he says.

And this is exactly what makes ketamine unique as an antidepressant, says Dr. Krystal.

However, as the nasal spray becomes available via prescription, patients have questions: How does it work? Is it safe? And who should get it? Read on for answers.

How do antidepressants work?

Research into ketamine as an antidepressant began in the 1990s with Dr. Krystal and his colleagues Dennis Charney, MD, and Ronald Duman, PhD, at the Yale School of Medicine. At the time (as is still mostly true today) depression was considered a “black box” disease, meaning that little was known about its cause.

One popular theory was the serotonin hypothesis, which asserted that people with depression had low levels of a neurotransmitter called serotonin. This hypothesis came about by accident—certain drugs given to treat other diseases like high blood pressure and tuberculosis seemed to drastically affect people’s moods. Those that lowered serotonin levels caused depression-like symptoms; others that raised serotonin levels created euphoric-like feelings in depressed patients. This discovery ushered in a new class of drugs meant to treat depression, known as selective serotonin reuptake inhibitors (SSRIs). The first one developed for the mass market was Prozac.

But eventually it became clear that the serotonin hypothesis didn’t fully explain depression. Not only were SSRIs of limited help to more than one-third of people given them for depression, but growing research showed that the neurotransmitters these drugs target (like serotonin) account for less than 20 percent of the neurotransmitters in a person’s brain. The other 80 percent are neurotransmitters called GABA and glutamate.

GABA and glutamate were known to play a role in seizure disorders and schizophrenia. Together, the two neurotransmitters form a complex push-and-pull response, sparking and stopping electrical activity in the brain. Researchers believe they may be responsible for regulating the majority of brain activity, including mood.

What’s more, intense stress can alter glutamate signaling in the brain and have effects on the neurons that make them less adaptable and less able to communicate with other neurons.

This means stress and depression themselves make it harder to deal with negative events, a cycle that can make matters even worse for people struggling with difficult life events.

Ketamine—from anesthetic to depression “miracle drug”

Interestingly, studies from Yale research labs showed that the drug ketamine, which was widely used as anesthesia during surgeries, triggers glutamate production, which, in a complex, cascading series of events, prompts the brain to form new neural connections. This makes the brain more adaptable and able to create new pathways, and gives patients the opportunity to develop more positive thoughts and behaviors. This was an effect that had not been seen before, even with traditional antidepressants.

“I think the interesting and exciting part of this discovery is that it came largely out of basic neuroscience research, instead of by chance,” says Gerard Sanacora, MD, PhD, a psychiatrist at Yale Medicine who was also involved in many of the ketamine studies. “It wasn’t just, ‘let’s try this drug and see what happens.’ There was increasing evidence suggesting that there was some abnormality within the glutamatergic system in the brains of people suffering from depression, and this prompted the idea of using a drug that targets this system.”

For the last two decades, researchers at Yale have led ketamine research by experimenting with using subanesthetic doses of ketamine delivered intravenously in controlled clinic settings for patients with severe depression who have not improved with standard antidepressant treatments. The results have been dramatic: In several studies, more than half of participants show a significant decrease in depression symptoms after just 24 hours. These are patients who felt no meaningful improvement on other antidepressant medications.

Most important for people to know, however, is that ketamine needs to be part of a more comprehensive treatment plan for depression. “Patients will call me up and say they don’t want any other medication or psychotherapy, they just want ketamine, and I have to explain to them that it is very unlikely that a single dose, or even several doses of ketamine alone, will cure their depression,” says Dr. Sanacora. Instead, he explains, “I tell them it may provide rapid benefits that can be sustained with comprehensive treatment plans that could include ongoing treatments with ketamine.  Additionally, it appears to help facilitate the creation new neural pathways that can help them develop resiliency and protect against the return of the depression.”

This is why Dr. Sanacora believes that ketamine may be most effective when combined with cognitive behavioral therapy (CBT). CBT is a type of psychotherapy that helps patients learn more productive attitudes and behaviors. Ongoing research, including clinical trials, addressing this idea are currently underway here at Yale.

A more patient-friendly version

The FDA-approved drug esketamine is one version of the ketamine molecule, and makes up half of what is found in the commonly used anesthetic form of the drug. It works similarly, but its chemical makeup allows it to bind more tightly to the NMDA glutamate receptors, making it two to five times more potent. This means that patients need a lower dose of esketamine than they do ketamine. The nasal spray allows the drug to be taken more easily in an outpatient treatment setting (under the supervision of a doctor), making it more accessible for patients than the IV treatments currently required to deliver ketamine.

But like any new drug, this one comes with its cautions. Side effects, including dizziness, a rise in blood pressure, and feelings of detachment or disconnection from reality may arise. In addition, the research is still relatively new. Studies have only followed patients for one year, which means doctors don’t yet know how it might affect patients over longer periods of time. Others worry that since ketamine is sometimes abused (as a club drug called Special K), there may be a downside to making it more readily available—it might increase the likelihood that it will end up in the wrong hands.

Also, esketamine is only part of the treatment for a person with depression. To date, it has only been shown to be effective when taken in combination with an oral antidepressant. For these reasons, esketamine is not considered a first-line treatment option for depression. It’s only prescribed for people with moderate to severe major depressive disorder who haven’t been helped by at least two other depression medications.

In the end, though, the FDA approval of esketamine gives doctors another valuable tool in their arsenal against depression—and offers new hope for patients no one had been able to help before.

To learn more, visit yalemedicine.org.

Should I Seek Help?

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“Doing it yourself is a fad in the United States.”  These were the first words in my first book in psychology, which I coauthored more than 40 years ago.  Turns out we were wrong.  Doing it yourself is not a fad, but a way of life in the U.S.  These days we have so many more resources available to help us help ourselves, including self-help blogs like this one.  And, of course, YouTube, which is a wonderful resource for training videos.  I’ve turned to YouTube to learn the basics of such tasks as caulking a bathroom tub and repairing a hinge on kitchen cabinets. There’s pride in doing things yourself, even if the quality of the work may not match that of a professional.  But I would draw the line at developing a winning tennis serve by following a self-instructional tutorial.  Sometimes a good coach is needed.  There is also a line to be drawn between using the Internet for self-help—even blogs like this—and seeking professional help.

My first book in the field focused on applying principles of behavior therapy to problems in living, from losing excess weight to smoking cessation to overcoming fears and sexual problems.  For many of the problems people encounter in their daily lives, behavior therapy offered practical solutions. This blog continues in that tradition, offering tips for changing your thoughts and attitudes to change your life.  We have explored how to rethink your responses to life’s twists and turns, and along the way offered tips on a range of troubling emotions, from overcoming worry and guilt to coping with fear and managing anger.  We applied the wisdom of ancient Greece to “know thyself” by turning inwardly to examine and evaluate our thoughts and beliefs, especially the negative thoughts that underlie emotional problems like anxietydepression, and anger. We confronted the two worthless emotions, worry and guilt—worthless because we don’t need to be wracked with guilt to recognize our mistakes and correct them or to be consumed with worry to take steps to protect ourselves from impending threats.

Self-Care Is Self-Help

With all this emphasis on self-help, we can lose sight of the importance of a basic principle of self-care—seeking help from others when help is needed.  But how do you know when going it alone is just not cutting it?  The benchmark clinicians typically use is whether problems are persistent and cause significant emotional stress or impair daily functioning.  If you regularly struggle to get out of bed and get going in the morning because you’re feeling down in the dumps, your state of mind is affecting your ability to function effectively.  If you can’t shake off intrusive worrisome or guilt thoughts, or if angry outbursts damage your relationships with others, or if you are continually on edge and can’t sleep at night or relax during the day, then it’s clear your daily functioning is impaired.

Where to Turn for Help

In the forty or so years I’ve been in practice, I’ve witnessed many changes in the field, including the emergence of cognitive behavioral therapy (CBT) as the leading modality of psychotherapy in use today. When I began my practice, psychodynamic therapists schooled in the Freudian and neo-Freudian traditions dominated the field. Today, there are many different forms of therapy and many different types of therapists, from psychologists and psychiatrists to mental health counselors and clinical social workers.  Some forms of therapy, like CBT, offer briefer and more problem-focused treatment approaches than traditional therapies, such as psychoanalysis.  CBT has become the treatment of choice for a range of psychological problems from phobias to social anxiety to insomnia, and evidence from controlled trials shows that CBT more than holds its own when stacked up against other therapies for treating depression and other emotional disorders and when compared to psychiatric medication.

Over the years, the field of psychiatry has become increasingly medicalized, as psychiatrists (medical doctors with specialized training in psychiatry) largely turned from practicing psychotherapy toward medication management. Though psychiatric drugs have important roles to play in the treatment of mental health disorders, especially so with more severe disorders such as bipolar disorder and schizophrenia, popping a pill does not help people solve problems in their daily lives or learn skills they need to change how they think or improve their relationships with others. Moreover, relapse rates are high when patients stop taking psychiatric meds, and for good reason, as these drugs help manage symptoms but do not address underlying emotional or interpersonal problems. On the other hand, patients can carry the techniques they learn in psychotherapy well beyond the course of treatment and continue to apply them in their daily lives.

Am I Ready to Reach Out?  A 10-Item Checklist

If you’re thinking about whether it makes sense to seek help from a professional, you may find the following checklist to be a useful guide. There is no set number of items that determine whether you could benefit from seeking help.  But as a general guideline, answering at least a few of these questions in the affirmative suggests it might be helpful to talk to a psychologist or other mental health professional.

Yes or No? (You be the Judge)

1.       Are my efforts to change my thinking or attitudes working?

2.       Do I continue to struggle with anxiety, depression, or other negative feelings that impact my daily functioning?

3.       Am I able to step back and examine my own thoughts, or would it help to have another person’s perspective?

4.       Do I give up too easily rather than persevere in changing my thoughts and behaviors?

5.       Are other people telling me I would benefit from “talking to somebody”?

6.       Are worries making it difficult to sleep or function effectively during the day?

7.       Am I avoiding situations out of fear or anxiety?

8.       Is my behavior affecting my relationships in negative ways?

9.       Do I find it difficult to make changes on my own or to stick with them?

10.     Might I work better with a professional than going it alone?

Finding a Therapist

If you do decide to seek help, select a therapist who best fits your needs.  Do you want to work with a therapist who uses psychological methods of treatment, such as a psychologist or counselor, or would benefit more from psychiatric medication prescribed by a psychiatrist?

Find a practitioner with the appropriate licensure and credentials—for example, a licensed psychologist, or a licensed psychologist holding advanced credentials (e.g., a Diplomate in Clinical Psychology awarded by the American Board of Professional Psychology, or ABPP), or a board-certified psychiatrist.  Find out whether your medical insurance covers mental health services (check it out with your health care provider) and whether are you covered for out-of-network providers.  As with other specialists, you may need to pay the therapist’s fee upfront and be reimbursed afterwards if the services are covered by your insurance plan, less any deductibles, co-pays, and so on.

Word of mouth is a good source for finding a therapist but be aware that what works well for one person might not work for another.  You might also “google” the practitioner to see if anything untoward turns up or ask your state licensing board if there are any complaints filed against the individual. Be prepared to ask a potential therapist a lot of questions, like whether the therapist is experienced in treating people with similar problems as your own, what specific form of treatment will be used and what evidence supports its effectiveness,  how long treatment is expected to last, what adverse experiences might be expected, such as drug side-effects, whether you are responsible for cancellation fees, and so on.  Licensed professionals will openly discuss these and other questions with potential clients.  If they balk, take that as a sign to look for someone else.

Whether you try going it alone or reaching out for help, the good news is that there is a range of effective therapeutic techniques that can help people live happier and more fulfilling lives.

© 2019 Jeffrey S. Nevid