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What is the context of this research?

Up to 1/3 of people with major depression may not respond to multiple antidepressant treatment attempts. They suffer severe emotional, social, economic, and medical consequences, and they are at a high risk of suicide. Ketamine, a 50 year old medication, given as a single intravenous infusion, produces dramatic reductions in depression symptoms within hours among those who have been refractory to treatment.

Since 2011, Dr. Levine has treated approximately 400 patients with very promising results, and this treatment is growing in acceptance and availability around the world. What remains unanswered are the aspects of ketamine's diverse mechanism that account for its unique effect. This is particularly timely, as multiple products based upon ketamine's mechanism are now in development.

What is the significance of this project?

One question in particular has been the importance of the experience of transient dissociation, a dreamlike state, during an infusion. There has been conflicting data on the association between this perceptual state and antidepressant response, and most of the new products in development seek to eliminate this as an inconvenient side effect.

The exploration of ketamine's effects has focused mainly on a target in the brain called the NMDA receptor and the triggering of events that promote regrowth and healing of the damaging effects of depression. However, ketamine also has anti-inflammatory properties, and measuring markers of inflammation may help predict treatment response. The role of inflammation in depression has been considered and several anti-inflammatory drugs have shown promise.

What are the goals of the project?

Recent research has looked at the role of positive emotions in inflammation, and found an association between the experience of awe, an emotion combining dread, veneration, and wonder inspired by the sacred or sublime, and reduced inflammatory markers. Having listened to thousands of accounts of ketamine infusions, patients often give very rich descriptions of their experience, and a sense of awe is commonly reported. However, not everyone will have this experience.

We hypothesize that the experience of awe is positively correlated with antidepressant response. The answer to this question, using a blinded study of 30 subjects and independently measuring depression and awe, has a bearing both on optimizing the effectiveness of this treatment, as well as future antidepressant development.