No laughing matter: Laughing gas for treating depression

While the nickname ‘laughing gas’ sounds like something that might cheer people up, it’s only recently that it’s been taken seriously as a possible tool for treatment-resistant depression.Indeed, nitrous oxide is one of several anesthetics generating excitement as new ways to treat depression. Nitrous oxide, ketamine, propofol, sevoflurane and isoflurane are all being investigated for possible roles in clinical depression. Ketamine is already used in many places for this purpose.When it comes to anesthetics for depression “right now ketamine is the rock star, but nitrous oxide is very promising,” said Dr. Beverley Orser, an anesthesiologist and professor of medicine at the University of Toronto and coauthor of a paper in Anesthesiology discussing general anesthetic drugs for depression. There are multiple reasons why anesthetic drugs show promise—leading to a lag in considering them for this indication. Intriguingly, they target different receptors in the brain than current antidepressants.Generally, antidepressants (including selective serotonin reuptake inhibitors) target the monoamine system. They “typically require weeks or months to take effect, and are associated with adverse effects that reduce drug adherence,” the paper said.Anesthetics including ketamine and nitrous oxide primarily work by blocking N-methyl D-aspartate (NMDA) to lead to loss of consciousness and analgesia—though they also target additional receptors. But dysregulation of the NMDA system can contribute to mood disorders and anxiety, suggesting where possible connections between anesthesiology and psychiatry may exist.“Currently, it remains unclear whether the antidepressant properties of general anesthetic agents result from a single common pathway or multiple different mechanisms. All anesthetic drugs generally modify the balance between excitation and inhibition in the central nervous system, and regional changes in excitation and inhibition balance have been described in the context of major depressive disorder,” the paper said.It all started with ketamine which was discovered in 1956. Long used for sedation and pain management, it wasn’t until the year 2000 that it leapt to the fore as a possible treatment for depression. That’s when a small placebo controlled trial of seven patients with major depressive disorder (MDD) were given a single dose of either placebo or a low dose of ketamine.The results surprised everyone. The patients given ketamine not only improved quickly, but the effect lasted for several days. Since then, multiple trials have been conducted, the use of ketamine for MDD has become relatively widespread, and in 2019 the FDA approved esketamine for depression. Esketamine is an intranasal version of ketamine that is combined with a conventional oral antidepressant. Because of adverse side-effects, its approval requires that it be given in a restrictive clinical setting where patients are under the supervision of physicians. However, the National Health Service in Great Britain rejected its approval in that country because of concerns about possible side effects. “What’s clear is these drugs are having rapid but sustained antidepressant properties, which persist long after the drug and the drug metabolites have been eliminated. But what’s equally interesting is that they don’t seem to have the same effect on the normal healthy brain,” Dr. Orser said. They may not be as effective in people with milder depression.It also leads to the idea that “there is something that is dysregulated in depression and the drugs are righting a wrong. That’s very interesting because the drugs are also providing insights into the biology of the dysregulation that’s causing depression,” Dr. Orser told the Medical Post.That there are lingering drug effects has upset some traditional ideas in anesthesiology, such as the belief that once an anesthetic drug has dissipated, it is eliminated from the brain and the brain goes back to baseline state. Recent studies are showing there are longer effects, as well possible increased risk of neurocognitive changes and possibly dementia in older patients who get general anesthesia.Whether it’s laughing gas or ketamine, the drugs need to be treated with respect because of various risks associated with their administration. Even if the doses are substantially smaller than what’s used for anesthesia.“They need to be prescribed by a physician and the drug should only be administered carefully to patients who are appropriately selected by a psychiatrist in an environment where patients are properly monitored and cared for,” she said.Several studies have looked at nitrous oxide as an antidepressant. Two trials of were patients with MDD and showed that a single, one hour treatment with nitrous oxide led to a rapid and significant reduction in depression scores relative to placebo. Dr. Orser was a coauthor of a double-blind randomized controlled trial led by psychiatrist Dr. Benjamin Goldstein from the University of Toronto, where low-dose inhaled nitrous oxide was compared to intravenous midazolam in patients with bipolar depression. Concurrent magnetic resonance imaging (MRI) during drug administration was done to examine blood flow in the brain as an indicator of treatment response. The results showed a significant reduction in depression scores in both treatment groups, but there was a greater same-day reduction in depression severity in the nitrous oxide group. However, the improvements didn’t persist at a 24-hour assessment.Anesthetic drugs such as ketamine are also used to treat pain, raising the question of whether pathways involved in depression are also involved in pain. Or whether depression can be seen as a variation of physical pain.Indeed, according to a Harvard Health newsletter, “people with chronic pain have three times the average risk of developing psychiatric symptoms, often mood or anxiety disorders, and depressed patients have three times the average risk of developing chronic pain.”It also stated that “Pain, especially chronic pain, is an emotional condition as well as a physical sensation. It is a complex experience that affects thought, mood and behavior and can lead to isolation, immobility and drug dependence,” it said. Several antidepressants are used to treat pain.While there is still much more to be learned, “the main message is this is a really exciting field,” Dr. Orser said.

No laughing matter: Laughing gas for treating depression

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