Tag: depression

Low Doses of Nitrous Oxide can Relieve Stubborn Depression

A small dose of nitrous oxide may be able to relive the symptoms of medication-resistant depression. Photo by Mockup Graphics on Unsplash

A new study at the University of Chicago Medicine and Washington University found that inhaling low doses of nitrous oxide gas rapidly relieved symptoms of treatment-resistant depression, with few adverse side effects. They found that this was as effective as higher doses of the gas, with fewer unpleasant side effects.

These findings add to the growing body of evidence of non-traditional treatments that may be a viable option for patients with depression that is unresponsive to typical antidepressant medications. It may also be a fast-acting and effective treatment option for patients in crisis.

Often called ‘laughing gas’, nitrous oxide is widely used as an anaesthetic, providing short-term pain relief in dentistry, emergency response and surgery.

A previous study tested a one-hour inhalation session with 50% nitrous oxide gas, which resulted in rapid improvements in depressive symptoms that lasted for at least 24 hours. However, several patients reported negative side effects, including nausea, vomiting and headaches.

“This investigation was motivated by observations from research on ketamine and depression,” said Peter Nagele, MD, Chair of Anesthesia and Critical Care at UChicago Medicine. “Like nitrous oxide, ketamine is an anaesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

The new study used a similar protocol with 20 patients, this time adding an additional inhalation session with 25% nitrous oxide. They found that the halved-concentration treatment was nearly as effective as 50% nitrous oxide, but there were only one quarter of the negative side effects.

Additionally, researchers tested the patients’ depression scores following treatment over a longer period of up to two weeks compared to 24 hours in the previous protocol. Surprisingly, they found that after only a single administration, some patients had improvements that lasted for the entire follow-up period.

“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” said Dr Nagele. “This has never been shown before. It’s a very cool finding.”

These findings point to nitrous oxide being a promising, rapid and effective treatment for those suffering from severe depression which is unresponsive to the usual medication such as SSRIs.

“A significant percentage — we think around 15% — of people who suffer from depression don’t respond to standard antidepressant treatment,” said Charles Conway, MD, Professor of Psychiatry and Director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine. “These ‘treatment-resistant depression’ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

Despite its ‘laughing gas’ name, patients actually fall asleep after such a low dose.

“They’re not getting high or euphoric, they get sedated,” Dr Nagele said.

Non-traditional treatments for depression faces an uphill battle for acceptance in the mainstream, though researchers hope that the findings from this and similar studies will help open physicians’ minds towards these other possible solutions.

“These have just been pilot studies,” said Dr Nagele. “But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”

With broader public acceptance, Dr Nagele hopes that these results help those patients who are struggling to find adequate therapies for their depression.

“There is a huge unmet need,” he said. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality. If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that’s a very gratifying line of research.”

Source: University of Chicago Medical Center

Journal information: P. Nagele et al., “A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression,” Science Translational Medicine (2021). 

Inflammation a Predictor of Future Depression in Widowed Spouses

Researchers at Rice University have found that future depression in widowed spouses can be predicted by bodily inflammation after the death of their partners.

The study will be published in the June 2021 edition of the journal Psychoneuroendocrinology. The study was led by lead author Lydia Wu, a Rice psychology graduate student, and Christopher Fagundes, associate professor of psychology and principal investigator for the Biobehavioral Mechanisms Explaining Disparities (BMED) lab at Rice. The researchers recruited 99 participants who had lost their spouses within 2-3 months of the study, and evaluated them on a number of factors, including physical and mental health, over three months.

“Prior research has already linked bodily inflammation to a host of health issues, including cancer, memory issues, heart problems and depression,” Wu said. “We were interested in how systemic inflammation affects the mental health of spouses after losing a loved one. In particular, can inflammation help us identify who will experience clinical levels of depression at a future point in time?”

The researchers found that widowed spouses with higher levels of bodily inflammation immediately after the loss of their partners had more severe symptoms of depression three months later compared to those with lower inflammation levels. This was even more pronounced if they didn’t experience significant depression initially.

Prof Fagundes said that it is normal to experience depression following the death of a spouse, and research shows that undergoing psychotherapy right after the event can actually interfere with people’s natural coping ability.

“We know that most people are remarkably resilient,” he said.

In the case of persistent depression, or depression occurring six or more months after a spouse’s death, it may be a sign that clinical intervention is needed, Prof Fagundes said.

“Until this study, it was difficult to know who was at risk for these persistently high levels of depression and grief until the six-month mark,” he said. “This study identifies a potential biomarker that could help us predict who is at greatest risk for long-term repercussions of loss.”

“This information makes early intervention possible,” Wu said. “We can identify at-risk bereaved persons and introduce them to interventions early on to improve their mental health.”

The researchers said more research is needed to determine who might be at greatest risk.

Source: Rice University

Journal information: E. Lydia Wu et al, Inflammation and future depressive symptoms among recently bereaved spouses, Psychoneuroendocrinology (2021). DOI: 10.1016/j.psyneuen.2021.105206

Zuranolone, a New Drug for MDD Shown to Be Safe and Effective in Trials

A recent trial showed that nightly 30mg doses of zuranolone, a new drug to treat major depressive disorder (MDD), are safe and only requires about two courses to achieve clinical improvement.

Zuranolone is one of a new class of neuroactive steroid drugs that positively modulates GABAA receptors. It has high bioavailability, can be taken orally and has a half-life suitable for daily administration. 

The SHORELINE Study is a Phase III, open-label, one year longitudinal study to evaluate the safety, tolerability, and need for repeat dosing with zuranolone in adults with MDD. Two cohorts with either zuranolone 30mg or 50mg as a starting dose taken once nightly for 14 days. Need for repeated dosing is assessed every 14 days based on a patient-reported assessment, with a maximum of five courses over a year.

Analysis of the data showed that the study’s primary endpoint of safety and tolerability show that zuranolone was generally well-tolerated in both dosage cohorts, with adverse events being generally consistent with those seen in previous zuranolone trials.

Secondary endpoints included response and remission as evaluated by the 17-item Hamilton Rating Scale for Depression (HAMD-17) and the number of times a patient received retreatment. A mean of 2.2 treatments resulted in patients with a clinical response (baseline HAMD-17 reduction of ≥50%) to the initial course of zuranolone 30mg. Additional data from patients in the 50 mg dose cohort is expected to be reported in late 2021.

“Sage embarked on the LANDSCAPE clinical program to evaluate the safety and efficacy of zuranolone with the ambition of reimagining the treatment for depression with the goal of a rapid-acting, durable, treat-as-needed option in a disease where innovation is lacking and the incidence rate has unfortunately increased exponentially in the last 20 years,” said Barry Greene, Chief Executive Officer at Sage Therapeutics. “Today we are announcing additional positive data from the SHORELINE Study that demonstrate continued strong results from the 30 mg dose and strengthens our confidence in the potential of the 50 mg dose. Designed as a naturalistic study, these data approximate real-world evidence of use of zuranolone at 30 mg and 50 mg doses. We look forward to the results of the WATERFALL and CORAL Phase 3 pivotal data readouts in MDD this year.”

Source: Sage Therapeutics