Nitrous oxide targets brain circuits involved in mood

NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits

This research will test whether inhaled nitrous oxide changes brain connectivity and improves symptoms in adults with treatment-resistant major depression compared with healthy volunteers.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Washington University School of Medicine (other)
• Locations: 1 site (St Louis, Missouri)
• Trial ID: NCT02994433 on ClinicalTrials.gov

What this trial studies

The trial will enroll about 25 adults with treatment-resistant major depression and about 25 non-depressed healthy volunteers who are right-handed and aged 18–65. Each participant will be exposed to nitrous oxide and a placebo gas while undergoing functional connectivity MRI to compare effects on affective brain circuits. Depressed participants must have HDRS ≥17 and documented failure of ≥3–4 adequate antidepressant trials; controls must have HDRS ≤7 and no history of depression. The goal is to link nitrous oxide’s clinical effects to specific changes in brain network connectivity.

Who should consider this trial

Good fit: Adults 18–65 with treatment-resistant major depression (HDRS ≥17) who have failed ≥3–4 adequate antidepressant treatments, are right-handed, English-speaking, and have no other major psychiatric or primary neurological disorders.

Not a fit: People with other DSM‑IV Axis I diagnoses (besides MDD for the TRMD group), primary neurological disorders, or those who are not right-handed or outside the 18–65 age range are unlikely to benefit from participating.

Why it matters

Potential benefit: If successful, this work could point to rapid-acting treatments or specific brain circuit targets for people whose depression has not responded to standard therapies.

How similar studies have performed: A recent pilot study from the same group reported antidepressant effects of nitrous oxide in treatment‑resistant depression, while using neuroimaging to map mechanisms is a newer step.

Eligibility criteria

Inclusion Criteria:

* Adults 18-65 years of age
* Right-handed
* Controls: Not meet The Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder (MDD) by scoring ≤7 on the Hamilton Depression Rating Scale (HDRS), 17-item; Treatment-Resistant Major Depression (TRMD) patients: Must meet a ≥17 score on the HDRS.
* Controls: Must not have any history of depression as determined by reported history and medical record review; TRMD: Documented (chart review) failure to respond to ≥3-4 adequate dose/duration antidepressant treatments; ≥1 in the current depressive episode.
* Good command of the English language

Exclusion Criteria:

* Meets criteria for any DSM-IV Axis I diagnosis as documented in medical records and as determined by structured clinical interview (except MDD for the TRMD group)
* Known primary neurological disorders or medical disorders including dementia, stroke, encephalopathy Parkinson's Disease, brain tumors, multiple sclerosis, seizure disorder, severe cardiac or pulmonary disease
* Any central nervous system active medication as determined by study investigator
* Any known disease affecting drug metabolism and excretion (e.g. renal or liver disease) as determined by study investigator
* Left-handedness
* Not eligible for MRI scans (e.g. history of claustrophobia/implanted metal as per MRI Screening Tool)
* Current use of psychotropic medications, antidepressants, or prescription or non-prescription drugs/herbals intended to treat depression or anxiety (control group only)
* Any recent (within past 12 months) history of substance dependence or abuse, determined by reported history or urine drug screen
* Ability to become pregnant and not using effective contraception
* Contraindication against the use of nitrous oxide:

  1. Pneumothorax
  2. Bowel obstruction
  3. Middle ear occlusion
  4. Elevated intracranial pressure
  5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12
  6. Pregnant patients
  7. Breastfeeding women
* Inability to provide informed consent
* Any other factor that in the investigators' judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from clinic).

Where this trial is running

St Louis, Missouri

• Washington University School of Medicine — St Louis, Missouri, United States (RECRUITING)

Study contacts

• Principal investigator: Charles R Conway, MD — Washington University School of Medicine
• Study coordinator: Britt Gott, MS

Conditions: Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant