Ketamine for Major Depression: New Tool, New Questions – Harvard Health Blog

Ketamine was once mainly used as anesthetic on battlefields and in the operating rooms. Now, this drug is gaining ground as a promising treatment for some cases of major depression, the leading cause of disability in the world. In the United States, recent estimates indicate that 16 million adults have had an episode of major depression over the course of a year. Suicide rates rose sharply between 1999 and 2016, increasing by more than 30% in 25 states. Because of its rapid action, ketamine may play a role in preventing suicide.

Why is ketamine exciting for treating depression?

If a person responds to ketamine, they can quickly reduce the risk of suicide (life-threatening thoughts and actions) and relieve other serious symptoms of depression. Ketamine can also be effective in treating depression associated with anxiety.

Other treatments for suicidal thoughts and depression often take weeks or even months, and some people have to try several medications or approaches to get relief. This is true for conversation therapies, antidepressants, transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT), which is currently the most effective treatment for major depression that does not respond to other treatments.

Are there different types of ketamine?

Ketamine is primarily used in the treatment of major depression that has failed to respond to two or more drugs (treatment-resistant depression).

• Racemic ketamine, which is most often administered by infusion into the blood. This is sometimes called intravenous ketamine or IV. It is a mixture of two mirror image molecules: ketamine "R" and "S". Although it was approved as an anesthetic by the FDA several decades ago, it is used off-label to treat depression.
• The esketamine (Spravato), approved by the FDA in March, is administered by nasal spray. It uses only the molecule "S".

Until now, most research has focused on ketamine infusions.

Both forms of ketamine interact differently with receptors in the brain. The delivery of ketamine and the type given affect the effectiveness of the drug and the side effects. We do not yet know which type is the most effective and to what extent adverse effects may differ. Further research comparing efficacy and side effects is needed.

How does ketamine work?

The operation of ketamine is not entirely clear. As it exerts an antidepressant effect through a new mechanism, ketamine can help people successfully manage depression when other treatments have not worked.

A 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 the connections in another receptor, called the AMPA receptor. Together, the initial blocking of NMDA receptors and the activation of AMPA receptors lead to the release of other molecules that help neurons to communicate with each other in new ways. Known as synaptogenesis, this process probably affects mood, thought patterns and cognition.

Ketamine can also affect depression in another way. For example, this could reduce the signals involved in inflammation, which has been linked to mood disorders, or facilitate communication in specific areas of the brain. Most likely, ketamine works in several ways at once, many of which are under study.

What are the possible side effects of ketamine?

All drugs have side effects. When a person is suicidal or severely depressed, the potential benefits may outweigh the potential risks.

Ketamine administered by infusion can cause:

• high blood pressure
• nausea and vomiting
• perception disturbances (time seeming to accelerate or slow down, colors, textures and sounds that seem particularly stimulating, blurred vision)
• dissociation (sometimes called out-of-body experiences) rarely can a person feel like looking down, for example.

In general, any change in perception or dissociation is particularly noticeable during the first infusion and ends very quickly thereafter.

Esketamine nasal spray can cause the same side effects. However, the timing and intensity of these effects are different.

Frequent or long-term 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 administered for depression compared to the dose needed for anesthesia.
• Like opioids, ketamine has addictive properties. It is important to understand this when assessing risks and benefits. If you have a history of substance abuse – such as alcohol or drugs – it is especially important that you and your doctor determine if ketamine is a good option for you.
• When ketamine IV (racemic) is effective, people respond with one to three infusions. If a person does not react at all, it is unlikely that any other infusions will help. Instead, it is probably best to try other treatments for depression.
• People who experience some relief after one or three ketamine treatments are likely to extend these positive effects if the treatment is repeated several times. The following sessions may help prolong the effects of ketamine, rather than getting additional symptom relief. There are no standard guidelines for this. Many studies initially offer eight treatments (acute phase). After that, the patient and the doctor decide to gradually reduce or stop the ketamine treatments or to continue the treatments at longer intervals.

For more information on ketamine

National Institute of Mental Health

FDA