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Nitrous Oxide for Major Depressive Disorder

Primary Purpose

Depressive Disorder, Major Depressive Disorder, Treatment Resistant Depression

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Nitrous Oxide

Placebo

About this trial

This is an interventional treatment trial for Depressive Disorder focused on measuring Nitrous Oxide, Laughing Gas

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Adult (≥18 years, both sexes), with ICD-10 criteria for MDD without psychosis, as determined by a structured clinical interview Mini International Neuropsychiatric Interview
Moderate to severe depression, as defined by a pretreatment score >17 on the HDRS-17 scale
TRD was defined as having had at least two adequate dose-duration, antidepressant medication failures in the current episode and a lifetime failure of at least three antidepressant medication trials.
Informed consent to participate in this study

Exclusion Criteria:

A history of bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses; active suicidal intention, as determined by clinical interview
Active or recent (<12 months) substance abuse or dependence; excluding nicotine
Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease
Acute severe suicidal ideation
Acute psychosis
Received ECT treatment within 6 months
History of NMDA-antagonists (e.g., ketamine) intake
Pregnancy or breastfeeding
Any contraindications to the use of nitrous oxide (e.g., pneumothorax, middle ear occlusion, elevated intracranial pressure, chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).

Sites / Locations

Mental Health Institute & Faculty of Psychiatry of The Second Xiangya Hospital, Central South University

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Air oxygen mixture

Nitrous oxide

Arm Description

participants in this arm inhale mixed oxygen-air gas (inspired oxygen concentration ~50%).

Participants in this group inhale mixed 50% nitrous oxide and 50% oxygen.

Outcomes

Primary Outcome Measures

Change in Hamilton Depression Rating Scale-17 item (HDRS-17)

Interview-based questionnaire used to measure the severity of depression. Consists of 17 items with a score calculated. Higher scores are associated with more severe depression. 0 - 7 = Normal; 8 - 17 = Mild Depression; 18 - 24 = Moderate Depression; > 25 = Severe Depression; Maximum score = 52

Change in QIDS-16-SR (Quick Inventory of Depressive Symptomatology-16 Self Report)

This is a 16-item self report questionnaire that measures depressive symptoms. Improvement is reported in change in depressive score score ranges from 0-27, with higher numbers indicating more severe symptom reporting. Change is calculated by baseline plus/minus the value at the later time point

Change in Visual Analog Scale-Depression (VAS-D)

All patients are asked to fill out visual analog scale for depression (VAS-D) before and after the intervention. VAS-D is a self-report scale for ddepression severity, with 0 score indicating not at all depressed and 10 score indicating extremely depressed.

Secondary Outcome Measures

Chang in Event Related Potentials (ERPs)

The investigator employ 64-lead Event Related Potentials (ERPs) to assess the resting-state EEG signal and signals during specific neurocognitive processes related to tasks, including an emotional face recognition task, a dot probe task and a self-referential personality word memory task.

Change in voxel-based morphometry of grey matter, white matter as assessed by structural magnetic resonancce imaging.

Participants will receive resting-state functional magnetic resonance imaging (MRI). Scans will be performed on a 3.0-T Siemens Magnetom Skyra scanner (Siemens Healthineers, Erlangen, Germany). During scanning, all participants were instructed to remain motionless, and to think of nothing in particular but to not fall asleep.

Change in Functional connectivity

Change in Functional connectivity of the brain networks between baseline and after the inhaled Nitrous oxide 24hours as assessed by measure of connectivity in multimodal MRI.

Change in peripheral blood cytokines

Peripheral blood sample will be collected and the concentration of IL-6, TNF-α, and CRP will be assessed.

Change in feces bacterial flora

The objective of investigator is to characterize gut microbiome in patients with TRD. To explore the specific diversity of gut microbiome. The stool samples were collected in the collection kits at the baseline, and were frozen at -80 °C. After the process of DNA Purification, 16S rRNA Gene Amplification and Illumina MiSeq sequencing, the study finally find the abundance and diversity of microbiota.

Change in the TMT/A and B (Executive Function)

Trail Making Test (TMT) is a cognitive test designed to assess scanning, visuomotor tracking, executive function, and cognitive flexibility. It consists of two parts, A and B: the patient must draw lines to connect consecutively numbered circles (part A) and then connect consecutively numbered and lettered circles alternating between the two sequences (part B). The time taken to complete the two parts is recorded. Part A assesses cognitive processing speed. The lower the score the faster the processing speed.

Change in Congruent STROOP Time to Complete (Executive Function)

Stroop Colour Naming Test (STROOP) is a cognitive test designed to assess the ability to inhibit a prepotent response to reading words while performing a task that requires attention control. It comprises two sheets with 50 words on each, and each word is the name of a colour. On the first sheet, the Congruent STROOP Sheet, the word and ink colour match; on the Incongruent STROOP Sheet, the word and ink colour do not match. For each sheet, the patient has 4 minutes to name the ink colour of each word. When the patient finishes the sheet, or once 4 minutes is up, the clinician notes the time taken and counts the number of correct and incorrect responses. The scale ranges from 0-100, the higher score the greater the cognitive flexibility.

Digit-Span Test

Score range 0-12 for each of for dimensions: Digit span forward, digit span backward, block span forward, block span backward. Higher scores indicate better cognitive performance.

Change in DSST (Number of Correct Symbols)

Digit Symbol Substitution Test (DSST) is a cognitive test designed to assess psychomotor speed of performance requiring visual perception, spatial decision-making, and motor skills. It consists of 133 digits and requires the patient to substitute each digit with a simple symbol in a 90-second period. Each correct symbol is counted, and the total score ranges from 0 (less than normal functioning) to 133 (greater than normal functioning)." as a description of DSST.

Improvement on Snaith-Hamilton Pleasure Scale (SHAPS)

The Snaith-Hamilton Pleasure Scale (SHAPS) assesses the anhedonia symptoms of MDD patients, with higher score indicating more severe anhedonia. Evaluating the patient's pleasure experience and choosing the degree of agreement with the happy response in some pleasant situations, and each item was rated on a 4-point scale."1 = Strongly agree, 2 = agree, 3 = disagree and 4 = strongly disagree" This scale evaluates the status of patients in the recent period of time, The total score of the scale is the sum of the scores of 14 items, with a total score of 14-56. The higher the total score, the more serious the anhedonia.

Change in Hamilton Anxiety Rating Scale (HAM-A)

Assessed via the Hamilton Anxiety Rating Scale (HAM-A). The HAM-A score ranges from 0 (no present anxiety) to 56 (maximum anxiety score).

Full Information

NCT ID

NCT03932825

First Posted

April 20, 2019

Last Updated

April 7, 2021

Sponsor

Lingjiang Li

1. Study Identification

Unique Protocol Identification Number

NCT03932825

Brief Title

Nitrous Oxide for Major Depressive Disorder

Official Title

A Clinical Trial of Nitrous Oxide for Treatment-Resistant Major Depressive Disorder

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

April 1, 2019 (Actual)

Primary Completion Date

March 31, 2021 (Actual)

Study Completion Date

March 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Lingjiang Li

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

This study aims at investigating the persistence of antidepressant effect of Nitrous Oxide (N2O) for Treatment-Resistant Depression(TRD). The investigators also aim to assess the effect of N2O on the electroencephalograph, multimodal magnetic resonance imaging(MRI), blood cytokines, feces bacteria flora and neuropsychological performance in patients with TRD. The investigators further aim to identify the predictors of N2O's antidepressant effeect using the above techniques.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Depressive Disorder, Major Depressive Disorder, Treatment Resistant Depression, Depressive Disorder, Major, Depression

Keywords

Nitrous Oxide, Laughing Gas

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

44 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Air oxygen mixture

Arm Type

Placebo Comparator

Arm Description

participants in this arm inhale mixed oxygen-air gas (inspired oxygen concentration ~50%).

Arm Title

Nitrous oxide

Arm Type

Experimental

Arm Description

Participants in this group inhale mixed 50% nitrous oxide and 50% oxygen.

Intervention Type

Drug

Intervention Name(s)

Nitrous Oxide

Other Intervention Name(s)

Laughing Gas, Xiao Qi, 笑气

Intervention Description

An 1-hour session of inhaled nitrous oxide at concentrations of 50%.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Air oxygen mixture

Intervention Description

An 1-hour session of mixed oxygen-air gas(inspired oxygen concentration ~50%)

Primary Outcome Measure Information:

Title

Change in Hamilton Depression Rating Scale-17 item (HDRS-17)

Description

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Title

Change in QIDS-16-SR (Quick Inventory of Depressive Symptomatology-16 Self Report)

Description

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Title

Change in Visual Analog Scale-Depression (VAS-D)

Description

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Secondary Outcome Measure Information:

Title

Chang in Event Related Potentials (ERPs)

Description

Time Frame

Baseline, 24hours, 7days, 2weeks

Title

Change in voxel-based morphometry of grey matter, white matter as assessed by structural magnetic resonancce imaging.

Description

Time Frame

Baseline, 24hours

Title

Change in Functional connectivity

Description

Change in Functional connectivity of the brain networks between baseline and after the inhaled Nitrous oxide 24hours as assessed by measure of connectivity in multimodal MRI.

Time Frame

Baseline, 24hours

Title

Change in peripheral blood cytokines

Description

Peripheral blood sample will be collected and the concentration of IL-6, TNF-α, and CRP will be assessed.

Time Frame

Baseline, 2hours, 24hours

Title

Change in feces bacterial flora

Description

Time Frame

Baseline

Title

Change in the TMT/A and B (Executive Function)

Description

Time Frame

Baseline, 24hours, 7days, 2weeks

Title

Change in Congruent STROOP Time to Complete (Executive Function)

Description

Time Frame

Baseline, 24hours, 7days, 2weeks

Title

Digit-Span Test

Description

Score range 0-12 for each of for dimensions: Digit span forward, digit span backward, block span forward, block span backward. Higher scores indicate better cognitive performance.

Time Frame

Baseline, 24hours, 7days, 2weeks

Title

Change in DSST (Number of Correct Symbols)

Description

Time Frame

Baseline, 24hours, 7days, 2weeks

Title

Improvement on Snaith-Hamilton Pleasure Scale (SHAPS)

Description

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Title

Change in Hamilton Anxiety Rating Scale (HAM-A)

Description

Assessed via the Hamilton Anxiety Rating Scale (HAM-A). The HAM-A score ranges from 0 (no present anxiety) to 56 (maximum anxiety score).

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Other Pre-specified Outcome Measures:

Title

Change in Heart Rate Variability

Description

The investigator will assess the heart rate variability (HRV) of all participants before and after the intervention.

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Title

Number of Participants With Adverse Events AEs

Description

AEs are any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, or laboratory or physiologic observations occurring in a person given study treatment. The event does not need to be causally related to the study treatment.

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

Title

Clinician-Administered Dissociative States Scale (CADSS) Scores During inhaled nitrous oxide

Description

The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before inhaled, and 2hours and 24hours after the inhaled. The timeframe is "at this moment". Change From Baseline in Clinician-Administered Dissociative States Scale (CADSS) Score.

Time Frame

Baseline, 2hours, 24hours

Title

Suicidal ideation as assessed by the Scale for Suicide Ideation (SSI)

Description

The scale contains 19 items rated on a scale from 0 to 2, allowing score range from 0 to 38, score over 4 (first five items) will be considered inclusion criteria. Higher values indicate worsening or presence of suicidal ideation. Item 4 and 5 at the end of the last week was assessed. If the answer to both questions was "no", the patient was judged to have no suicidal ideation.If either answer is "weak" or "moderate to strong," it is considered suicidal ideation.The intensity of suicidal ideation was judged according to the mean value of items 1-5 in the scale. The higher the score, the greater the intensity of suicidal ideation.The risk of suicide was assessed according to items 6-19 of the suicide ideation scale.The total score was calculated by [(the sum of item 6-19 scores -9)/33]*100. The higher the score, the greater the risk of suicide.

Time Frame

Baseline, 2hours, 24hours, 7days, 2weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Adult (≥18 years, both sexes), with ICD-10 criteria for MDD without psychosis, as determined by a structured clinical interview Mini International Neuropsychiatric Interview Moderate to severe depression, as defined by a pretreatment score >17 on the HDRS-17 scale TRD was defined as having had at least two adequate dose-duration, antidepressant medication failures in the current episode and a lifetime failure of at least three antidepressant medication trials. Informed consent to participate in this study Exclusion Criteria: A history of bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses; active suicidal intention, as determined by clinical interview Active or recent (<12 months) substance abuse or dependence; excluding nicotine Presence of acute medical illness that could interfere with study participation, including significant pulmonary disease Acute severe suicidal ideation Acute psychosis Received ECT treatment within 6 months History of NMDA-antagonists (e.g., ketamine) intake Pregnancy or breastfeeding Any contraindications to the use of nitrous oxide (e.g., pneumothorax, middle ear occlusion, elevated intracranial pressure, chronic cobalamin or folate deficiency unless treated with folic acid or vitamin B12).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lingjiang Li, MD

Organizational Affiliation

Mental Health Institute, the Second Xiangya Hospital of Central South University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mental Health Institute & Faculty of Psychiatry of The Second Xiangya Hospital, Central South University

City

Changsha

State/Province

Hunan

ZIP/Postal Code

410001

Country

China

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Nitrous Oxide for Major Depressive Disorder

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