Elsevier

Psychiatry Research

Volume 322, April 2023, 115072
Psychiatry Research

Brain function changes reveal rapid antidepressant effects of nitrous oxide for treatment-resistant depression:Evidence from task-state EEG

https://doi.org/10.1016/j.psychres.2023.115072Get rights and content

Highlights

  • This study provides the EEG evidence that nitrous oxide-induced brain function changes for treatment-resistant depression (TRD).

  • This study firstly evaluated the efficacy of nitrous oxide for TRD based on event-related potential (ERP) components and functional connectivity networks (FCNs) methods.

  • These findings may suggest that nitrous oxide improves depression symptoms for TRD by altering brain function.

  • The network metrics in FCNs may provide new biological explanations for studying the rapid antidepressant effects of nitrous oxide on brain function.

Abstract

Nitrous oxide has rapid antidepressant effects in patients with treatment-resistant depression (TRD), but its underlying mechanisms of therapeutic actions are not well understood. Moreover, most of the current studies lack objective biological indicators to evaluate the changes of nitrous oxide-induced brain function for TRD. Therefore, this study assessed the effect of nitrous oxide on brain function for TRD based on event-related potential (ERP) components and functional connectivity networks (FCNs) methods. In this randomized, longitudinal, placebo-controlled trial, all TRD participants were divided into two groups to receive either a 1-hour inhalation of nitrous oxide or a placebo treatment, and they took part in the same task-state electroencephalogram (EEG) experiment before and after treatment. The experimental results showed that nitrous oxide improved depressive symptoms better than placebo in terms of 17-Hamilton Depression Rating Scale score (HAMD-17). Statistical analysis based on ERP components showed that nitrous oxide-induced significant differences in amplitude and latency of N1, P1, N2, P2. In addition, increased brain functional connectivity was found after nitrous oxide treatment. And the change of network metrics has a significant correlation with decreased depressive symptoms. These findings may suggest that nitrous oxide improves depression symptoms for TRD by modifying brain function.

Introduction

Treatment-resistant depression (TRD), as a severe form of major depressive disorder (MDD), is a complex intractable mental disorder. At present, there is still no highly consensus definition for it in medicine (Sforzini et al. 2021). The clinical characteristics of TRD are that patients do not respond significantly to multiple standard antidepressants or psychotherapies (Fogelson and Leuchter 2017) (Fabbri et al. 2021). Statistically, about 10% to 30% of the depressed patient population are completely unresponsive to antidepressant therapy (Tundo et al. 2015) (Huang et al. 2019). It may lead to diminished social functioning, increased psychiatric comorbidity and mortality. Therefore, it is urgent to find an effective therapeutic method for TRD.

Recently, a new study reported that nitrous oxide (“laughing gas”) has remarkable efficacy in rapidly relieving symptoms for TRD patients (Nagele et al. 2021). Nitrous oxide, a colorless, sweet-smelling gas, has a mild anesthetic effect, which is often used as an anesthetic in surgery. Given the similar mechanisms of action with ketamine, nitrous oxide also has the function of regulating N-Methyl-d-Aspartate (NMDA) receptor, which is an effective NMDA receptor antagonism (Chen et al. 2018). NMDA receptor plays an important role in the neurobiological study of depression and is a key component of information processing in the central nervous system (Duman and Aghajanian 2012) (Anita et al. 2011). Importantly, altered NMDA receptor function has been involved in pharmacological models and treatments of depression (Murrough and Charney 2010). This appears to be a strong biological principle in supporting the potential therapeutic use of nitrous oxide for TRD. Moreover, nitrous oxide has fewer side effects than ketamine, which makes it a better alternative for antidepressants (Zorumski et al. 2015) (Zarate and Machado-Vieira 2015). However, the underlying mechanisms regarding the therapeutic effects of nitrous oxide are unclear. And most of the current studies lack objective biological indicators to evaluate the changes of nitrous oxide-induced brain function for TRD.

With the development of imaging technology, electroencephalogram/event-related potential(EEG/ERP), magnetoencephalography(MEG), and functional magnetic resonance imaging (fMRI) have been widely used in the study of brain function for mental diseases such as depression. Among them, EEG/ERP has become one of the most effective data sources for decoding brain cognitive activities due to its advantages of high temporal resolution, good portability and non-invasive. Moreover, fast-growing research has shown that depression is a system-level disorder of brain function, which is clinically manifested as emotional cognitive impairment (Beck 2019). Emotional cognitive impairment of depression is associated with negative bias in affective stimuli and impaired emotion regulation (Beck and Bredemeier 2016) (Liu and Thompson 2017). Dai et al. found that sad faces induced higher P100 and P200 amplitudes in depressed patients than other emotional faces (Dai and Feng 2012). Hu et al. explored the effect of emotional face stimulation on attentional control of depressed patients based on dot-probe paradigm, and the experimental results showed that depressed patients had significantly enhanced N100, P200 and P300 amplitude, which indicated that negative emotional stimulation affected the attentional control function of depressed patients (Hu et al. 2017). These studies have proved that specific ERP components can effectively reflect the abnormal emotional cognitive processing of depressed patients.

The brain is a complex network structure that is affected by the interaction between multiple brain regions. Nowadays, analysis of brain functional connections based on EEG has been widely used in the clinical diagnosis of depression. An EEG study found that nitrous oxide can cause changes in the brain functional network (Foster and Liley 2011). Kuhlmann et al. found that nitrous oxide caused significant alterations in parietal level functional networks with an EEG study (Kuhlmann et al. 2013). In addition, a new study showed that alteration of brain network during nitrous oxide administration may be associated with the sedative mechanism of nitrous oxide (Lee et al. 2020). Therefore, understanding the state of the brain network during nitrous oxide sedation can help to understand the loss of consciousness and the mechanism of recovery for TRD.

This study aimed to investigate the effects of nitrous oxide on ERPs and FCNs for TRD during an emotional picture-recognition task. The specific research contents included the following two aspects: (1) Existing studies found specific ERP components could reflect the emotional cognitive impairment in MDD (Li et al. 2021). We hypothesized that nitrous oxide could impact the affective cognitive function in TRD. Therefore, we explored the changes of ERP components (P1, N1, P2, N2, P3) at different periods for TRD before and after treatment. In order to better explore the neural mechanism of nitrous oxide efficacy, standardized low resolution brain electromagnetic tomography (sLORETA) technology was used to trace the time periods with significant differences, so as to observe the location of relevant activated brain regions. (2) Previous studies have shown that cognitive dysfunction of MDD is related to abnormal functional connectivity in the brain (Li et al. 2022). We hypothesized that nitrous oxide would improve brain function of TRD to some extent. Therefore, we explored the effect of nitrous oxide on the FCNs of TRD before and after treatment. Besides, correlation analysis between the changes of network metrics and clinical characteristics was investigated.

Previous studies found that nitrous oxide had rapid antidepressant effects for TRD (Nagele et al. 2015). Zorumski et al. found that nitrous oxide can improve depression levels for TRD by inhibiting NMDA receptor function (Zorumski et al. 2015). Das et al. explored nitrous oxide as treatments for mood disorders, the results showed that nitrous oxide could regulate the brain emotional function of TRD to reduce the intrusive effects (Das et al. 2016). These findings provide direct evidence that nitrous oxide modulates brain function in TRD. But most studies lack objective physiological indicators to probe the effects. In this longitudinal study, we attempted to provide some potential biological evidence for nitrous oxide therapy in TRD based on EEG analysis. By studying the FCN and ERP characteristics of TRD patients in an emotional recognition task, we hypothesized that nitrous oxide may affect brain emotion-related functions to rapidly improve the degree of depression.

Section snippets

Participants

This study consisted of 44 participants who were recruited from the psychiatric department of the Xiangya Hospital Central South University (Changsha, Hunan Province of China). All participants were identified through participation in a secondary referral clinic for TRD. The inclusion criteria include:1. age 18–60 years old, and primary or higher educational level; 2. all patients received a structured Mini-International Neuropsychiatric Interview (MINI) that met Diagnostic and Statistical

Demographic and clinical characteristics

In this study, there are no significant differences on the demographic characteristics (T-test, p>0.05) between IG and CG. Hence, we performed a 2(times) × 2(groups) repeated-measures ANOVA on the score of HAMD. The results of the statistical test for HAMD showed a significant main effect of time (F = 121.23, p<0.001). The significant main effect of time demonstrated that the degree of depression was significantly decreased after treatment according to the scores of

ERPs findings induced by nitrous oxide

Previous ERP studies have confirmed the abnormal regulation of early affective expression in MDD (Dai and Feng 2012), which is similar to our findings. In this study, the experimental results found significant differences in the early ERP components (P1, N1, P2, N2) based on the emotional face paradigm before and after nitrous oxide treatment. Both N1 and P1 are related to the attention mechanism of individuals, and their amplitudes reflect the recognition and attention of individuals to the

Conclusions

Nitrous oxide, as an effective NMDA receptor antagonist, has been found a rapid antidepressant effect for TRD. However, objective evaluation is still lacking for the underlying functional mechanisms of nitrous oxide efficacy. Therefore, this study explored nitrous oxide-induced brain function changes for TRD based on the ERPs and FCNs. The experimental results found that significant statistical differences were concentrated in the early ERP components and FCNs before and after treatment in IG.

Data and code availability statement

The signed consent form of the patients did not include the permission for data sharing. Sharing the data could be arranged with a specific data sharing agreement upon reasonable request. All analyses were performed in Matlab or sLORETA using code from openly available software packages. If necessary, the original codes and EEG data are available on request to the corresponding author.

CRediT authorship contribution statement

Xuexiao Shao: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Danfeng Yan: Conceptualization, Methodology, Supervision, Validation. Wenwen Kong: . Shuting Sun: . Mei Liao: Supervision, Validation. Wenwen Ou: . Yan Zhang: . Fang Zheng: . Xiaowei Li: . Lingjiang Li: Conceptualization, Methodology. Bin Hu: Conceptualization, Methodology.

Declaration of Competing Interest

The authors declare no competing interests.

Acknowledgement

None.

Funding

This work was supported in part by STI 2030—Major Projects [No.2022ZD0208500], in part by the National Key Research and Development Program of China [Grant No.2019YFA0706200], in part by STI 2030—Major Projects [No.2021ZD0202000, No.2021ZD0200601], in part by the National Natural Science Foundation of China [Grant No.62102172, No.61627808, No.61632014], in part by Gansu Province Science and Technology Program [No.22JR5RA489], in part by Key Program of Natural Science Foundation of Gansu Province

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