Therapeutic Effects And Brain Functional Mechanisms Of Nitrous Oxide On Patients With Treatment-resistant Depression

Objective:To investigate the effect of nitrous oxide（N₂O）on treatment-resistant depression（TRD）,patients’cognitive function,and the mechanism of brain functional connectivity.Methods:Forty-four patients with TRD（who had experienced 2 failed sessions of treatment with antidepressants）were randomized to receive a1-hour inhalation of the mixture of either 50%N₂O/50%oxygen（the N₂O group,including 22 patients treated with N₂O）or 50%air/50%oxygen（the placebo group,including 22 patients treated with placebo）.All patients complete a general information questionnaire,and underwent a series of clinical and cognitive assessments.The 17-item Hamilton Depression Rating Scale（HAMD-17）,16-item Quick Inventory of Depressive Symptomatology（QIDS-16）,and visual analog scale for depression（VAS-D）were used to assess the severity of depression.Hamilton Anxiety Rating Scale（HAMA）and visual analog scale for anxiety（VAS-A）were used to assess the severity of anxiety.Snaith-Hamilton Pleasure Scale（SHAPS）was used to assess the severity of anhedonia.The Perceived Deficits Questionnaire for depression（PDQ-D）was used to assess the perceived cognitive symptoms.All the patients were required to complete their assessment with HAMD-17,HAMA,QIDS-16,SHAPS,VAS-A/D,and PDQ-D,as well as neurocognitive evaluation at 2 hours,24 hours,7 days,and 14 days after treatment.Resting-state and task-state EEG data for all the patients were collected at baseline and 24 hours,7 days,and 14 days after treatment.All EEG data were preprocessed with the EEGLAB kit.For resting-state microstates,the EEG data were analyzed using an EEGLAB plug-in（EEGLAB＿Microstates Version 0.3）.The connectivity was analyzed for the resting-state and task-related EEG data using the multi-signal coupling method.Results:1.Efficacy of nitrous oxide in patients with TRD Twenty-two patients in the placebo group and 22 patients in the N₂O group completed the clinical assessment,cognitive measurement,and EEG data acquisition at baseline and 4 time points in the follow-up period,i.e.,at 2 hours,24hours,7 days,and 14 days after treatment.At the end of the study,19patients in the placebo group and 16 patients in the N₂O group were included in the final analysis.In this study,we found that:（1）single inhalation of N₂O for one hour can alleviate the depressive symptoms(F_（4,29）=4.204,P=0.008)and anxiety symptoms(F_（1,32）=6.253,P=0.018)for TRD after 2h treatment.There was no significant difference in efficacy with regard to anxiety and depression between the N₂O group and the placebo group(F_（1,32）=0.077,P=0.783),and the effect of N₂O in improving depressive and anxiety symptoms might have lasted no more than 24 hours;（2）N₂O neither affect the subjective experience of anhedonia in patients with TRD(F_（1,32）=0.067,P=0.797),nor produce clinically significant dissociative symptoms(F_（2,40）=0.431,P=0.651);and（3）only two patients（9%）experienced acute gastrointestinal reactions such as nausea and vomiting during this study,and no other adverse reactions occurred.2.Influence of nitrous oxide on the cognitive functions of patients with TRD Compared with placebo,N₂O was associated with improvement in partial cognitive processing speed(F_（1,31）=4.303,P=0.046),sustained attention(F_（1,31）=7.856,P=0.009),and inhibitory control(F_（3,29）=5.597,P=0.001)in TRD.N₂O was also associated with improvement in subjective cognitive experience of the patients in 24 hours after treatment.3.Effect of nitrous oxide on the characteristics of EEG microstates in TRD From the range of changes in parameters,EEG microstates showed progressive features in TRD.Single inhalation of N₂O was mainly associated with changes in the mean duration(F_（1,30）=14.352,P<0.001),occurrence(F_（3,28）=8.545,P<0.001),and coverage(F_（3,28）=16.097,P<0.001)of microstate class D,and the occurrence(F_（3,28）=6.238,P=0.002)and coverage(F_（3,28）=3.675,P=0.024)of microstate class C.The therapeutic effect of N₂O on depressive symptoms might be related to the increase of the mean duration of microstate class D（r=0.474,P=0.030）.4.Effect of nitrous oxide on brain networks in TRD Compared with the placebo,N₂O treatment was associated with enhanced functional connectivity in the right frontal,left frontotemporal cross-correlation function in alpha band.There were differences in functional connectivity of related brain regions to different emotional stimuli in patients with TRD.Compared with positive emotional stimuli,negative emotional stimuli might be enhanced functional connetivity in the right frontal,left frontotemporal.Conclusions:1.A single inhalation of N₂O for 1 hour may produce an antidepressant effect by rapidly reducing anxiety symptoms and did not produce a sustained antidepressant effect in patients with TRD.A single inhalation of N₂O for 1 hour did not affect the subjective experience of anhedonia.There were no obvious adverse effects.2.N₂O could improve the cognitive processing speed,sustained attention,and inhibitory control,as well as subjective cognitive experience after treatment in patients with TRD.3.The parameters of EEG microstates showed a wider range was associated with functional impairment.EEG microstate and functional connectivity techniques can be used to evaluate the efficacy of rapid onset in patients with depression and provide evidence for further screening of specific indicators.