Ketamine for major depression: New tool, new questions

First things first: You may be asking yourself, "What is ketamine?" Well, it  was once used mainly as an anesthetic on battlefields and in operating rooms. Now this medication is gaining ground as a promising treatment for some cases of major depression, which is the leading cause of disability worldwide. In the US, recent estimates show 16 million adults had an episode of major depression in the course of a year. Suicide rates rose substantially between 1999 and 2016, increasing by more than 30% in 25 states. Because of its rapid action, ketamine could have a role to play in helping to prevent suicide.

Why is ketamine exciting for treating depression?

If a person responds to ketamine, it can rapidly reduce suicidality (life-threatening thoughts and acts) and relieve other serious symptoms of depression. Ketamine also can be effective for treating depression combined with anxiety.

Other treatments for suicidal thoughts and depression often take weeks or even months to take effect, and some people need to try several medications or approaches to gain relief. This is true for talk therapies, antidepressant medicines, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT), which is currently the most effective treatment for major depression that fails to respond to other therapies.

Are there different types of ketamine?

Two main types of ketamine are used to treat major depression that hasn't 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-image molecules: "R" and "S" ketamine. While it was approved decades ago as an anesthetic by the FDA, it is used off-label to treat depression.
• Esketamine (Spravato), which the FDA approved in March, is given as a nasal spray. It uses only the "S" molecule.

Thus far, most research has been on ketamine infusions.

The two forms of ketamine interact differently with receptors in the brain. The delivery of ketamine and the type given affect drug effectiveness and side effects. We don't yet know which type is more effective or how much side effects may differ. Further research comparing effectiveness and side effects is needed.

How does ketamine work?

It's not entirely clear how ketamine works. Because it exerts an antidepressant effect through a new mechanism, ketamine may be able to help people successfully manage depression when other treatments have not worked.

One likely target for ketamine is 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 connections in another receptor, called the AMPA receptor. Together, the initial blockade of NMDA receptors and activation of AMPA receptors lead to the release of other molecules that help neurons communicate with each other along new pathways. Known as synaptogenesis, this process likely affects mood, thought patterns, and cognition.

Ketamine also may influence depression in other ways. For example, it might reduce signals involved in inflammation, which has been linked to mood disorders, or facilitate communication within specific areas in the brain. Most likely, ketamine works in several ways at the same time, many of which are being studied.

What are the possible side effects of ketamine?

All drugs have side effects. When someone is suicidal or severely depressed, possible benefits may outweigh possible risks.

Ketamine given by infusion may cause:

• high blood pressure
• nausea and vomiting
• perceptual disturbances (time appearing to speed up or slow down; colors, textures, and noises that seem especially stimulating; blurry vision)
• dissociation (sometimes called out-of-body experiences); rarely, a person may feel as if they are looking down on their body, for example.

Generally, any changes in perception or dissociation are most noticeable during the first infusion and end very quickly afterward.

Esketamine nasal spray may cause the same side effects. However, the timing and intensity of those effects is different.

Long-term or frequent use of ketamine may have additional side effects. More research on this is needed.

What else should you know about ketamine?

• A much lower dose of ketamine is given for depression compared with the dose necessary for anesthesia.
• Like opioids, ketamine has addictive properties. It's important to understand this when weighing risks and benefits. If you have a history of substance abuse –– such as alcohol or drugs –– it's especially important for you and your doctor to consider whether ketamine is a good option for you.
• When IV (racemic) ketamine works, people usually respond to it within one to three infusions. If a person has no response at all, further infusions are unlikely to help. Instead, it's probably best to try other treatments for depression.
• People who experience some relief from depression within one to three ketamine treatments are probably likely to extend these positive effects if the treatment is repeated several more times. The subsequent sessions may help prolong the effects of ketamine, rather than achieving further dramatic relief of symptoms. There are no standard guidelines for this. Many studies offer eight treatments initially (acute phase). After this, patient and doctor decide whether to taper or stop ketamine treatments or continue treatments at longer intervals.