Inhaled gases for treatment-resistant major depression

Nitrous oxide for major depressive disorder

Similar to ketamine, which has rapid efficacy for treatment-resistant depression, nitrous oxide is a highly potent N -methyl- d -aspartate receptor (NMDAR) antagonist. This knowledge, along with the well-established euphoric effects of nitrous oxide, prompted speculation that it may have clinical antidepressant effects.

conducted a proof-of-concept double-blind, prospective, cross-over trial of 20 TRMD patients using inhaled nitrous oxide. TRMD patients underwent serial treatments with an hour-long inhalation with either 50% nitrous oxide/50% oxygen (active treatment); or 50% nitrogen/50% oxygen (placebo). These sessions were randomized in order and separated by 1 week. To be eligible for the trial, patients had to have failed at least 2 adequate dose-duration antidepressant trials (confirmed by medical record review), and could not have recent history of substance abuse (past 12 months, except nicotine), any lifetime history of psychotic or bipolar illness, or severe personality disorder. Patients were allowed to maintain their existing antidepressant treatments but were requested not to start any new antidepressant treatment or modify their treatment dosage in the 4 weeks prior to trial entry. To avoid nitrous oxide’s potential euphoric effects being confounded with antidepressant effects, the group selected 24 h postinhalation as the primary endpoint for assessment of antidepressant effects. TRMD patients enrolled in the trial suffered from sustained and severe refractory MDD: patients had a mean of 19 years of lifetime MDD, history of 8 average failed antidepressant treatments, and 4 had a history of failing to respond to ECT.

The results of the pilot trial were promising. At 24 h postinhalation, there was a statistically significant reduction in depressive symptoms in those who had received nitrous oxide versus placebo. Those receiving nitrous oxide experienced a mean decrease of 5.5 points on the Hamilton Depression Rating Scale (HDRS; 95 CI − 2.5 to − 8.5 points) at 24 h. There were 4 TRMD patients achieving antidepressant response (≥ 50% reduction from baseline HDRS score) and one achieving remission at 24 h; whereas only one placebo patient achieved response, and no placebo patients achieved remission ( ).

Interestingly, not all antidepressant symptoms improved equally, i.e., certain depressive symptoms appeared to be more responsive than others to nitrous oxide, including anxiety, depressed mood, suicidal ideation, and guilt, which has directed future studies (see “ Future studies of nitrous oxide ” section below). Similar to the observations of ketamine’s rapid antidepressant effects in TRMD, the effects of a single inhalation of nitrous oxide were frequently sustained; several patients who were randomized to receive nitrous oxide first showed sustained antidepressant effects on assessment at 1 week. Hence, this prompted future cross-over studies of nitrous oxide in TRMD having longer durations between exposures.

Also of importance, nitrous oxide was well-tolerated; the side effects were infrequent, minor, and short-lived. These included nausea and vomiting (15%), headache (10%), and paradoxical anxiety (10%) in a small subset of patients.

Most recently, conducted a double-blind, randomized, cross-over dose finding study of nitrous oxide. In this trial, 24 patients with severe TRD were randomly assigned to receive a one-hour inhalation with either (1) 50% nitrous oxide, (2) 25% nitrous oxide, or (3) placebo (air/oxygen). The primary outcome was the Hamilton Depression Rating Scale (HDRS-21). Both nitrous groups combined demonstrated significant improvement versus placebo (P = 0.01); however, there was no acute difference in antidepressant effects between 25% and 50% nitrous oxide (P = 0.58). However, adverse events (nausea, headache, dissociative feeling) were statistically higher in the 50% group (P < 0.001). There was a suggestion that 50% nitrous may have had more sustained antidepressant benefit. Further study of optimal dose finding is warranted.

Though limited in scope, this study (and our group’s continued studies in this area) support that nitrous oxide may have several advantages over ketamine as a rapid acting antidepressant. Unlike ketamine, existing data do not support emergence of psychosis as a common side effect, and nitrous oxide inhalation does not influence systemic blood pressure. Though nitrous oxide does have limited abuse potential (see " Abuse potential of nitrous oxide " section below), it has considerably less addictive potential than ketamine. Last, given that nitrous oxide is not hepatically or renally metabolized, it is rapidly cleared from the system, allowing patients to safely operate motor vehicles following treatments, whereas ketamine has a markedly longer recovery time and requires a driver postadministration.

Clinical administration of nitrous oxide for TRMD

From a regulatory standpoint, nitrous oxide is not regulated by the Drug Enforcement Agency. Occupational Safety and Health Administration (OSHA) does not have standards for nitrous exposure. The National Institute for Occupational Safety and Health, NIOSH, however, has a recommended exposure limit of 25 ppm in closed rooms.

Potential effects on psychomotor and cognitive function in health care workers leads to the need of minimizing leaks in gas delivery circuits and adequate exhaust through wall-suction waste gas scavenging systems. Closely fitting masks minimize leakage around the face. Even with a closed system, nitrous oxide is not effective as a single-agent general anesthetic.

Medical grade nitrous oxide can be acquired from gas distributors as E -cylinder tanks that can be dispensed through FDA-approved inhalation circuits or anesthesia ventilators. Nitrous oxide and oxygen/air flow meters allow accurate dispensing. Proportioning systems link the flows of oxygen and nitrous oxide to prevent the administration of mixtures that would induce hypoxia. Infrared spectroscopic gas analyzers and infrared pulse oximeters allow additional safety monitoring for detecting potential hypoxemia. Suction and airway equipment should be readily available. Staff trained in administering sedatives and airway support ensure safety, as per American Society of Anesthesia guidelines on sedation and analgesia by nonanesthesiologists.

Patient preparation and selection may minimize the risk of adverse events even for short inhalations. Fasting guidelines should be considered to minimize the possibility of aspiration events. A history of motion sickness or postoperative vomiting may portend susceptibility to the side effect of nausea. Respiratory depressant effects of narcotics and sedatives are augmented by nitrous oxide. As nitrous oxide accumulates in tissues with collected air, it is contraindicated in patients with pneumothorax, pneumomediastinum, or gastrointestinal distention. Patients with B12 deficiency or particular mutations in the methylenetetrahydrofolate reductase ( MTHFR ) gene should be reconsidered given the inhibition of methionine synthase by nitrous oxide.

With adherence to these considerations the clinical administration of nitrous oxide can be administered safely for TRMD.

Putative potential mechanism of action of nitrous oxide in TRMD

Despite over 150 years of clinical use for analgesia and anesthesia, how nitrous oxide brings about its effects is not fully understood. Below we discuss possible mechanisms of action.