Depression

Breathing In a Better Mood?

Oxygen and nitrous oxide are investigational treatments for depression.

Posted Dec 17, 2020

Chris Slupski at Unsplash
Gas canisters
Source: Chris Slupski at Unsplash

While it may sound a little far-fetched, the use of inhaled gases to treat depressive disorders may be in our future. First off, consider oxygen, the molecule that makes up 21% of the atmosphere. Our cells (specifically the mitochondria within the cells) need oxygen to make energy, and we die very quickly without it. We know that some of the mitochondria in depressed brains aren’t functioning as well as in non-depressed brains, so could enriching their fuel supply treat the symptoms of depression?

At first glance this seems ridiculous, especially since people without respiratory problems generally walk around with their blood oxygen saturations at 96-100% already. Just breathing higher concentrations of oxygen through a nasal cannula, like in a fancy Oxygen Bar, doesn’t saturate hemoglobin any further because it can’t. The hemoglobin is already full.

However, about 5-10% of oxygen in the blood isn’t bound to hemoglobin, and breathing enriched oxygen can increase this amount, called oxygen tension or partial oxygen pressure. You can increase oxygen perfusion in the brain with inspired oxygen by a small but appreciable amount, even in people with normal lung function.

Dr. R. Haim Belmaker, in an Israeli study, randomized 51 adults with mild or moderate depression to breathing 35% oxygen or 21% oxygen via nasal cannula for seven hours every night for a month at the vigorous rate of five liters a minute. At the end of this trial, the folks receiving the 35% oxygen had reduced depression ratings on a standard scale, noting improvement mostly in anxiety and cognitive symptoms. These patients had experienced depression for an average of 11 years and were in stable treatment, and people with obesity, respiratory disease, or sleep apnea were excluded from the trial. Because increased partial oxygen pressure in the blood can cause capillaries in the heart to contract, this treatment is potentially dangerous in people with high blood pressure or other cardiovascular disease. Still, the potential of using oxygen for depression is exciting and hopefully more studies will follow.

Nitrous oxide, a gas commonly used in anesthesia, might treat depression in a different way than oxygen. Like the FDA-approved ketamine nasal spray, nitrous oxide can block the NMDA receptor. Since part of the pathology of several mental illnesses involves increased firing of the NMDA receptor, many blockers like ketamine are being investigated for clinical depression.

Researchers randomized 21 people with treatment-refractory depression to either 50/50 nitrous oxide and oxygen or 50/50 nitrogen and oxygen (control) for an hour. After one week, those who received the placebo first were given the nitrous oxide, and those who had been given nitrous oxide were given the placebo. Three people receiving nitrous oxide discontinued the therapy before the hour was complete, but the uncomfortable side effects (such as headache, nausea, and anxiety) were minor and temporary. All patients had vital signs, respiratory, and cognitive status monitored by an anesthesiologist in a way similar to how they would be monitored in an operating room to ensure safety, and patients were not allowed to leave for a two-hour recovery period. In addition, since nitrous oxide can inactivate vitamin B12, researchers measured plasma homocysteine levels before and after the treatment.

Patients who received the nitrous oxide had significant improvement in depressive symptoms at two hours and at 24 hours after the treatment, with particular improvement in feelings of guilt, suicidal thinking, and anxiety. Since these patients had ratings of severe depression at the time of the trial and had struggled with the illness for an average of 19 years, failing a median of eight antidepressant medications, the findings in the pilot trial were impressive. Nitrous oxide has the potential for abuse and, like oxygen, can be medically dangerous, but this therapy could be useful in hospitals or other closely monitored health care settings.

Both of these treatments are in very early stages of investigation, but since the global burden of depressive illness is high, resulting in poorer physical health, lower income, more unemployment, and greater all-cause mortality, any plausible new avenues to helping people feel better are worth exploring. Physicians have been using both oxygen and nitrous oxygen in patients for over a century, and the dangers of the treatments, while significant, are well understood. Will patients with refractory depression be visiting anesthesia clinics for nitrous oxide or taking home canisters of oxygen to breathe at night sometime in the future? Perhaps… if the results of these tiny trials are repeated in larger, carefully designed studies.

Copyright Emily Deans MD

Image credit: Chris Slupski at Unsplash.com