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First things first: You may be asking yourself, “What is ketamine therapy?” Well, it used to be used mainly as an anesthetic on battlefields and in operating rooms. Now the drug is being promoted as a promising treatment for some cases of major depression, the leading cause of disability worldwide. Recent estimates in the US show that 16 million adults have had an episode of major depression during the year. Suicide rates rose significantly between 1999 and 2016, increasing by more than 30% in 25 states. Because of its rapid onset of action, ketamine could play a role in suicide prevention.
Why is ketamine therapy exciting in the treatment of depression?
If a person responds to ketamine therapy, it can quickly reduce suicidality (life-threatening thoughts and actions) and relieve other severe symptoms of depression. Ketamine may also be effective in the treatment of depression combined with anxiety.
Other treatments for suicidal thoughts and depression often take weeks or even months to work, and some people need to try several medications or approaches to get relief. This applies to talk therapy, antidepressants, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT), which are currently the most effective treatments for major depression unresponsive to other therapies.
Are there different types of ketamine therapy?
Two main types of ketamine therapy are used to treat major depression that has not responded to two or more medications (treatment-resistant depression).
Racemic ketamine, which is most often given as an infusion into the bloodstream. This is sometimes called intravenous or IV ketamine. It is a mixture of two mirror molecules: “R” and “S” ketamine therapy. Although it was approved by the FDA decades ago as an anesthetic, it is used off-label to treat depression.
Esketamine (Spravato), which was approved by the FDA in March, is given as a nasal spray. It only uses the “S” molecule.
To date, most research has looked at ketamine infusions.
The two forms of ketamine interact differently with receptors in the brain. The delivery of ketamine and the type given affect the drug’s effectiveness and side effects. We don’t yet know which type is more effective or how much the side effects may vary. More research comparing efficacy and side effects is needed.
How does ketamine work?
It is not entirely clear how ketamine works. Because ketamine has an antidepressant effect through a novel mechanism, it may be able to help people successfully manage depression when other treatments have not worked.
One likely target for ketamine therapy is the NMDA receptors in the brain. By binding to these receptors, ketamine appears to increase the amount of a neurotransmitter called glutamate in the spaces between neurons. Glutamate then activates a connection in another receptor, called an AMPA receptor. The initial blockade of NMDA receptors and activation of AMPA receptors together lead to the release of additional molecules that help neurons communicate with each other along new pathways. This process, known as synaptogenesis, is believed to influence mood, thought patterns, and cognition.
Ketamine therapy can affect depression in other ways as well. For example, it can reduce signals involve in inflammation, which is link to mood disorders, or facilitate communication in specific areas of the brain. Ketamine most likely works in several ways simultaneously, many of which is study.
What are the possible side effects of ketamine?
All medications have side effects. When someone is suicidal or has severe depression, the potential benefits may outweigh the potential risks.
Infused ketamine therapy can cause:
- High blood pressure
- Nausea and vomiting
- Perceptual disturbances (time seems to speed up or slow down; colors, textures, and sounds that seem
- Particularly stimulating; blurred vision)
- Dissociation (sometimes called out-of-body experiences); rarely, one may feel as if one is looking down on one’s body, for example.
- Generally, any changes in perception or dissociation are most noticeable during the first infusion and then subside very quickly.
Esketamine nasal spray can cause the same side effects. However, the timing and intensity of these effects vary.
Long-term or frequent use of ketamine can have other side effects. More research is need on this topic.
What else should you know about ketamine therapy?
In depression, a much lower dose of ketamine is given compared to the dose required for anesthesia.
Like opioids, ketamine has addictive properties. This is important to understand when weighing the risks and benefits. If you have a history of substance abuse — such as alcohol or drugs — it’s especially important that you and your doctor consider whether ketamine is a good choice for you.
When IV (racemic) ketamine works, people usually respond to it within one to three infusions. If the person does not respond at all, further infusions are unlikely to help. Instead, it’s probably best to try other depression treatments.
People who experience some relief from depression within one to three ketamine treatments are likely to extend these positive effects if the treatment is repeated several more times. Subsequent sessions may help to prolong the effects of ketamine, rather than achieving further dramatic relief from symptoms. There are no standard guidelines for this. Many studies initially offer eight treatments (acute phase). After that, the patient and the doctor decide whether to reduce or stop the ketamine therapy treatment or to continue the treatment at longer intervals.
On March 5, 2019, the Food and Drug Administration (FDA) approved the first new drug for major depression in decades. The drug is a nasal spray called esketamine, derived from ketamine therapy, an anesthetic that has made waves for its surprising anti-depressant effects.
Ketamine Therapy Treatment
Because esketamine treatment can help the patients with treatment-resistant depression (meaning they haven’t help by standard treatments), the FDA has acceleratE the approval process to make it available more quickly. In one study, 70 percent of patients with treatment-resistant depression who start on an oral antidepressant and intranasal esketamine improve, compare with more than half in a group that receive no medication (the placebo group).
“This is a game changer,” says John Krystal, MD, chief psychiatrist at Yale Medicine and one of the nation’s pioneers in ketamine research. The drug works differently than those used before, he notes, calling ketamine an “anti-medication.” “With most drugs like valium, the anti-anxiety effect you get only lasts while it’s in your system. When the valium wears off, you can get anxiety. When you take ketamine, it triggers reactions in your cortex that allow brain connections to be re-established. It is the response to ketamine, not the presence of ketamine in the body, that creates its effects,” he says.
And that’s exactly what makes ketamine therapy unique as an antidepressant, says Dr. Krystal.
But when a nasal spray is available by prescription, patients have questions: How does it work? It is safe? And who should get it? Read the answers.
How do antidepressants work?
Research into ketamine as an antidepressant began in the 1990s with Dr. Krystal and colleagues Dennis Charney, MD, and Ronald Duman, PhD, at the Yale School of Medicine. At the time (as is mostly true today), depression consider a “black box” disease, meaning that little know about its cause.
One popular theory was the serotonin hypothesis, which claimed that people with depression have low levels of a neurotransmitter called serotonin. This hypothesis arose by chance – certain drugs given to treat other diseases, such as high blood pressure and tuberculosis, seemed to drastically affect people’s moods.
Those that lowered serotonin levels caused depression-like symptoms; others that increased serotonin levels produced euphoric feelings in depressed patients. This discovery ushered in a new class of drugs to treat depression, known as selective serotonin reuptake inhibitors (SSRIs). The first to develop for the mass market was Prozac.
Does Ketamine Therapy Treat Depression?
In the end, however, it turned out that the serotonin hypothesis does not fully explain depression. Not only did SSRIs provide only limited help to more than one-third of people with depression, but growing research has shown that the neurotransmitters these drugs target (such as serotonin) make up less than 20 percent of the neurotransmitters in the human brain. The other 80 percent is make up of neurotransmitters call GABA and glutamate.
GABA and glutamate know to play a role in seizure disorders and schizophrenia. Together, these two neurotransmitters form a complex push-and-pull response that starts and stops electrical activity in the brain. Scientists believe they may be responsible for regulating most brain activity, including mood.
What’s more, intense stress can alter glutamate signaling in the brain and affect neurons, making them less adaptable and less able to communicate with other neurons.
This means that stress and depression themselves make it harder to deal with negative events, a cycle that can make things worse for people who are dealing with difficult life events.
Ketamine – from anesthetic to depression “miracle drug”
Interestingly, studies from Yale research laboratories shows that the drug ketamine therapy, which has been widely use as an anesthetic in surgery, triggers the production of glutamate, which in a complex cascade of events prompts the brain to form new neural connections. This makes the brain more adaptable and able to create new pathways, giving patients the opportunity to develop more positive thoughts and behaviors. This was an effect not see before even with traditional antidepressants.
“I think the interesting and exciting part of this discovery is that it come largely out of basic neuroscience research, not by accident,” says Gerard Sanacora, MD, PhD, a psychiatrist at Yale Medicine who has also involve in much of the ketamine. studies.
Ketamine Therapy
“It wasn’t just, ‘Let’s try this drug and see what happens.’ There was mounting evidence to suggest that there was some abnormality in the glutamatergic system in the brains of people with depression, and that sparked the idea of using the drug. which targets this system.”
For the past two decades, Yale researchers have led ketamine research by experimenting with subanesthetic doses of ketamine administered intravenously in controlled clinical settings for severely depressed patients who have not improved with standard antidepressant treatment.
The results were dramatic: In several studies, more than half of the participants showed a significant decrease in depression symptoms after just 24 hours. These are patients who have not experienced any significant improvement on other antidepressants.
Ketamine and Depression
However, the most important thing for people to know is that ketamine therapy must be part of a more comprehensive treatment plan for depression. “Patients call me and say they don’t want any other drugs or psychotherapy, they just want ketamine, and I have to explain to them that it’s very unlikely that one dose or even several doses of ketamine alone will cure their depression,” says Dr. Sanacora.
Instead, he explains, “I tell them it can provide quick benefits that can sustain with comprehensive treatment plans that could include continue ketamine treatment. Additionally, it appears to help facilitate the creation of new neural pathways that can help them develop resilience and protect against the return of depression.
This is why Dr. Sanacora believes that ketamine therapy may be most effective when combined with cognitive behavioral therapy (CBT), a type of psychotherapy that helps patients learn more productive attitudes and behaviors. Research, including clinical trials, is currently underway at Yale to address this idea.
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