Research snapshot: Nitrous oxide may be linked to less severe depression symptoms among adults with treatment-resistant bipolar depression

What do you need to know?

There are few effective treatments for depression in individuals with bipolar disorder, especially fast-acting ones. Nitrous oxide, an anesthetic agent also known as laughing gas, has been shown to work quickly in a small set of studies of adults with treatment-resistant major depressive disorder. In this study, researchers compared the effect of a single treatment session of nitrous oxide against another anesthetic that is not known to have antidepressant effects, midazolam, in adults with treatment-resistant bipolar depression. The researchers also used magnetic resonance imaging (MRI) to measure blood flow in various brain regions before, during and after treatment. Results showed that participants who received nitrous oxide had less severe depression symptoms on the day of treatment compared to participants who received midazolam. However, the difference between these two groups was no longer significant 24 hours after treatment. The researchers also found that lower blood flow at baseline in a key region of the brain, the anterior cingulate cortex (which is involved in processing emotions and regulating behaviour) was associated with a greater reduction of depressive symptoms in participants who were treated with nitrous oxide compared to participants who were treated with midazolam.

What is this research about?

While episodes of mania, or milder episodes called hypomania, are the most distinguishing feature of bipolar disorder, it is actually depression that accounts for most of the symptoms of bipolar disorder in both youth and adults.

Numerous treatments are available for mania but few options exist for the treatment of bipolar depression, especially fast-acting treatments. Nitrous oxide has been shown to have fast-acting effects in adults with major depressive disorder whose symptoms did not improve with other treatments. Studies have also shown that this commonly used anesthetic increases blood flow in the brain, an important indicator of brain health. This effect is important because people with bipolar depression are known to have reduced brain blood flow.

Researchers conducted this study to compare the effect of a single treatment session of inhaled nitrous oxide against midazolam on depression symptoms and blood flow in the brain in adults with treatment-resistant bipolar depression.

What did the researchers do?

The researchers recruited 25 participants with an average age of 34 years. The participants had a primary diagnosis of bipolar disorder and were experiencing a major depressive episode for at least four weeks. They were also taking at least one anti-manic, mood-stabilizing medication.

Each participant was fitted with a close-fitting mask and an IV (short for intravenous line). They were randomized into one of two groups: 

To avoid potential negative events or risks, both the concentration of nitrous oxide and the duration of treatment were shorter than in previous depression studies, resulting in a total dose that was less than one-quarter of that in the prior studies. 

The researchers measured depressive and other psychiatric symptoms at the following time points:

They also used MRI to measure blood flow in brain regions and networks implicated in bipolar disorder and emotional regulation.

What did the researchers find?

Results showed that participants who received a single treatment session of nitrous oxide had less severe depression symptoms on the day of treatment compared to the midazolam group. The difference between these two groups was no longer significant 24 hours after treatment.

The researchers also found that lower blood flow at baseline in a key brain region, the anterior cingulate cortex, was associated with a greater reduction of depressive symptoms in participants treated with nitrous oxide compared to those treated with midazolam.

What were the limitations of the study?

The study had a small sample size due to recruitment challenges that stemmed from a combination of factors, including MRI-related exclusions, the need to coordinate study visits with participants together with team members from psychiatry, anesthesiology and brain imaging, and the onset of the COVID-19 pandemic. Also, researchers didn’t assign participants to a group where they weren’t exposed to a psychoactive anesthetic (i.e., IV saline plus inhaled room air). This limits their ability to determine if the reduction in depressive symptoms was due to treatment or a placebo effect related to the treatment they received.

What can this study be used for?

The findings provide a promising signal that further studies are worthwhile. In addition to the overall goal of reducing depression symptoms, there are other potential uses for nitrous oxide in bipolar disorder, including preventing the need for hospitalization or shortening the duration of hospitalization, and reducing suicidality. In addition, the researchers hope that this treatment can be extended to youth with bipolar depression.

This study also provides support for including neuroimaging tests that focus on blood flow in the brain in future psychiatric studies.

About the authors

William S.H. Kim1,2 , Mikaela K. Dimick 3,4,5 , Danielle Omrin 3,4 , Rachel H.B. Mitchell 4,5,6, Daniel Riegert 4,7, Anthony Levitt 2,4,6 , Ayal Schaffer 2,4,6 , Susan Belo 4,7 , John Iazetta4 , Garfield Detzler4 , Mabel Choi 4,7, Stephen Choi4,7, Nathan Herrman2,4,6, Roger S. McIntyre5,6,8, Bradley J. MacIntosh1,2, Beverly A. Orser2,4,7, Benjamin I. Goldstein3,4,5,6

  1. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  2. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
  3. Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
  4. Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
  5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  6. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
  7. Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.
  8. Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada.

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