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. 2025 Aug 28;15(8):e098281. doi: 10.1136/bmjopen-2024-098281

Intravenous administration of adenosine triphosphate combined with escitalopram in major depressive disorder: protocol for a randomised, double-blind, placebo-controlled trial

Qianqian Xin 1,2,3, Huafeng Wei 1,2,3, Dhirendra Paudel 1,2,3, Nengyuan Hu 2,3,4,5,6,7,8, Yuhan Zhao 1,2,3, Yuan Feng 1,2,3, Xian Luo 1,2,3, Meilei Su 1,2,3, Xiang Xue 1,2,3, Haokang Huang 1,2,3, Zhihong Lv 1,2,3, Chong Tang 1,2,3, Yongzhi Zhao 1,2,3, Miaoqin Tan 1,2,3, Xinyou Luo 1,2,3, Yun Yang 1,2,3, Qiuqu Liu 1,2,3, Minghong Huang 1,2,3, Yihong Cheng 1,2,3, Tianming Gao 2,3,4,5,6,7,8,*, Bin Zhang 1,2,3,✉
PMCID: PMC12410628  PMID: 40876882

Abstract

Introduction

Major depressive disorder (MDD) is the most prevalent mental illness. Antidepressants with rapid efficacy and acceptable tolerance have been investigated for many years. A preclinical study performed by our group revealed that the dysregulation of extracellular ATP is related to the pathophysiology of depression and that the medial prefrontal cortex-lateral habenula pathway is a potential cellular and neural circuit target for ATP involvement in depression-like behaviour. Moreover, through small-sample clinical trials, the group has preliminarily discovered the antidepressant effect of ATP. However, the antidepressant effects of and neural circuit mechanisms underlying ATP in depressed patients remain largely unexplored. This study pioneers the intravenous use of escitalopram in combination with oral escitalopram for the treatment of MDD, thus representing a new direction in antidepressant research.

Methods and analysis

This clinical study is a single-centre, randomised, double-blind, placebo-controlled, superiority trial involving 120 MDD patients evenly divided into two groups. The experimental group will receive an intravenous injection of 10 mL ATP in 100 mL normal saline (NS) two times per day (BD) for 2 weeks, whereas the control group will receive 110 mL NS BD for 2 weeks. All of the participants will take 10 mg of oral escitalopram daily for 4 weeks, with flexible adjustment thereafter based on clinical response. Our primary outcome will be the change in the Hamilton Depression Rating Scale 24 (HAMD-24) score from baseline to 2 and 4 weeks. The secondary outcomes assessment (at 1, 2, 4, 12 and 24 weeks) will be done by the Montgomery-Asberg Depression Rating Scale, HAMD-24, Hamilton Anxiety Scale, Beck Depression Inventory, Snaith-Hamilton Pleasure Scale, Clinical Global Impression, Insomnia Severity Index, Columbia-Suicide Severity Rating Scale, Side Effect Rating Scale of Asberg, MRI, cognitive function and cytokine level analyses.

Ethics and dissemination

The study protocol and all of the related materials were approved by the Institutional Ethics Committee of Nanfang Hospital, Southern Medical University (No. NFEC-2024-070, NFEC-2020-153, Guangzhou, China). Results will be disseminated through peer-reviewed publications and conference presentations.

Trial registration number

NCT06266715.

Keywords: Randomised controlled trial, major depressive disorder, ATP, adenosine triphosphate, escitalopram

STRENGTHS AND LIMITATIONS OF THIS STUDY.

  • A rigorously controlled 2-week inpatient protocol ensures medication adherence and safety monitoring.

  • Double-blind randomised allocation to intravenous ATP or normal saline for intervention bias.

  • Flexible antidepressant adjustment after 4 weeks reflects real-world clinical practice.

  • Extended 24-week follow-up captures long-term treatment outcomes.

  • Single-centre recruitment may limit population diversity and generalisability.

Introduction

Major depressive disorder (MDD) is a substantial public health concern that affects more than 300 million individuals worldwide. Depression is one of the leading causes of disability,1 and the relative risk of all-cause mortality for those individuals with depression is 1.7 times greater than the risk for the general public.2 In China, more than 54 million people (4.2% of the population) suffer from depression.3

Although effective antidepressants for treating depression are available, these drugs take time to elicit effects and are associated with patient adherence problems.4 Although many patients with depression can exhibit reduced or remitted symptoms after treatment with existing pharmacotherapies,5 approximately 30%–50% of patients do not respond fully, and as many as 10%–30% of patients are thought to be resistant to therapy, thus resulting in average effects that are only slightly greater than the effects of a placebo.6 7 Furthermore, there is still a need for a deeper understanding of the pathophysiology of depression and the development of novel treatments.

Generally, 50%–75% of patients with appropriate first-line pharmaceutical treatment demonstrate reduced symptoms, with the remainder of patients showing no improvement in their condition. After the initiation of treatment, symptoms usually begin to disappear 4–6 weeks later.8 9 A quick response to treatment may enhance patients’ confidence in their ability to overcome depression and help them in adhering to regular drug intake, hence reducing the risk of suicide and improving medication adherence. The treatment results will be more favourable if more progress is made during the early stages of treatment (particularly in the first 2 weeks).10 Therefore, scientists hope to discover antidepressants with rapid actions and few adverse effects.

The medial prefrontal cortex (mPFC), which is linked to many brain areas, is crucial for emotion regulation, including anxiety and depression.11,15 Growing evidence suggests that energy homeostasis at the cellular level is disrupted in the mPFC of individuals with depression16 17 and that this imbalance can be corrected by several antidepressant treatments.18,20 ATP, which is the main cellular energy source, is released by neurons and astrocytes to aid their communication.21,24 Both preclinical25,27 and clinical studies28,30 have shown that disruptions in extracellular ATP levels in the mPFC are involved in the pathology of depression.

The mPFC projects to several brain regions, including the dorsal raphe nuclei31,34 and lateral habenula (LHb),35,38 both of which are strongly linked to depression. The research team discovered that the direct activation of the mPFC-LHb pathway triggered depressive-like behaviours, whereas the inhibition of this pathway reduced depressive-like symptoms in chronic social defeat stress-susceptible mice and Itpr2-/- mice, as demonstrated via ex vivo slice electrophysiology, RNA interference, chemogenetic manipulations, gene knockouts and behavioural testing.39 However, the antidepressant effects and underlying neural circuit mechanisms of ATP in depressive patients are still unclear.

Compared with control conditions, randomised controlled trials (RCTs) are the ‘gold standard’ for assessing the effectiveness of interventions.40 In initial small-sample RCTs (NCT05431413 and NCT03138681), the research team has reported preliminary evidence suggesting that ATP may exert antidepressant effects. This study aims to more comprehensively validate the antidepressant effects and elucidate the neural circuit mechanisms of ATP by expanding the sample size and incorporating clinical scales, MRI, cognitive assessments and laboratory markers such as cytokines. This will be the first clinical trial to combine intravenous ATP administration with oral escitalopram in patients with MDD. The primary objective of this RCT is to evaluate the impact of ATP combined with escitalopram therapy in MDD patients.

Methods and analysis

Study design

This randomised (1:1), double-blind, controlled clinical trial is being conducted at Nanfang Hospital, Southern Medical University, Guangzhou, China. The trial protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials guidelines (online supplemental table 1), and the summary of the trial is provided in accordance with the WHO Trial Registration Data Set (online supplemental table 2). The Southern Medical University Nanfang Hospital Institutional Review Board approved this trial and will be monitored by an independent data monitoring committee. Written informed consent (online supplemental file 1 – informed consent) will be obtained from all of the participants (figure 1).

Figure 1. Study flow diagram. ANT, attention network test; BD, two times per day; BDI, Beck Depression Inventory; CGI, Clinical Global Impression; CRP, C reactive protein; C-SSRS, Columbia-Suicide Severity Scale Paediatric Version; DSI, diffusion spectral imaging; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; DTI, diffusion tensor imaging; HAMA, Hamilton Anxiety Scale; HAMD-24, Hamilton Depression Rating Scale 24; IL-6, interleukin-6; ISI, Insomnia Severity Index; MADRS, Montgomery-Asberg Depression Rating Scale; MDD, major depressive disorder; MID, monetary incentive delay task; NS, normal saline; OD, once daily; PVT, psychomotor vigilance task; QSM, quantitative susceptibility mapping; rs-fMRI, resting-state functional MRI; SERS, Side Effect Rating Scale; SHAPS, Snaith-Hamilton Pleasure Scale; TNF, Tumor Necrosis Factor; TNF-α, TNF-alpha.

Figure 1

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Participants

This study will include participants with moderate to severe MDD episodes, as assessed with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

Inclusion criteria

  • Meet the DSM-5 diagnostic criteria for moderate to severe MDD.

  • Hamilton Depression Rating Scale 24 (HAMD-24) scores ≥20.

  • 18–65 years old, irrespective of sex.

  • Participants who had not used any psychotropic medications within 1 month prior to the study and who never had treatments with escitalopram.

  • Individuals without contraindications to selective serotonin reuptake inhibitors.

  • Individuals without contraindications to ATP.

  • Written informed consent.

Exclusion criteria

  • Participants with various major mental disorders other than depression (bipolar disorders, psychotic disorders, personality disorders, alcohol use disorders, substance use disorders and disorders due to medical or organic causes) were assessed via the Chinese version of the Mini International Neuropsychiatric Interview (MINI).

  • Individuals with neurological disorders such as dementia.

  • Individuals with a high risk of suicide.

  • Pregnant and lactating women.

  • Contraindications to MRI.

  • An evaluation by a psychiatrist stating that the participants were not suitable for inclusion in this study.

Interventions

Participants fulfilling the study criteria will be randomly assigned to a control group (escitalopram plus normal saline (NS)) or an experimental group (ATP group, escitalopram plus ATP and NS) at a 1:1 ratio for treatment.

The control group will receive a tab of 10 mg escitalopram once daily (OD) after breakfast for 4 weeks and an injection of 110 mL NS BD ranging from after breakfast to before lunch and ranging from after lunch to before dinner for 2 weeks.

The ATP group will receive a tab of 10 mg escitalopram OD after breakfast for 4 weeks and an injection of 10 mL ATP in 100 mL NS BD ranging from after breakfast to before lunch and ranging from after lunch to before dinner for 2 weeks.

After 4 weeks, the medication of the subjects in both groups will be freely changed, and treatment will continue as advised by their psychiatrist. Patients will be hospitalised for the first 2 weeks, and outpatient treatment for the 4th, 12th and 24th weeks will be provided.

Outcomes

The primary outcome of this study is the change in the HAMD-24 score from baseline to 2 and 4 weeks.

The secondary outcome measures are as follows:

  • A response defined as an HAMD-24 score reduction of at least 50% compared with the baseline score.

  • Remission is defined as an HAMD-24 score ≤7.

  • Montgomery-Asberg Depression Rating Scale.

  • Hamilton Anxiety Scale (HAMA).

  • Beck Depression Inventory (BDI).

  • Snaith-Hamilton Pleasure Scale (SHAPS).

  • Clinical Global Impression (CGI), including severity, improvement (CGI-I) and efficacy index subscales.

  • Insomnia Severity Index (ISI).

  • Columbia-Suicide Severity Rating Scale (C-SSRS).

  • MRI, including diffusion tensor imaging, diffusion spectral imaging, quantitative susceptibility mapping, resting-state functional MRI and task-based fMRI (involving a monetary incentive delay task and emotional face processing task).

  • Cognitive functions, including the attention network test, the psychomotor vigilance task and the N-back task.

  • Cytokines, including interleukin-6, TNF-alpha and C reactive protein (CRP).

  • Side Effect Rating Scale (SERS) of Asberg.

Clinical scales will be evaluated from baseline to weeks 1, 2, 4, 12 and 24. MRI data will be evaluated from baseline to weeks 2 and 4. Cognitive functions and cytokines will be evaluated from baseline to weeks 2, 4, 12 and 24. All of the clinical scales will be used in the Chinese language and have been previously validated in the Chinese population.

Sample size

The sample size was calculated by using the Superior by a Margin Tests for the Difference Between Two Means module in Power Analysis & Sample Size (PASS) software. According to the pre-experiment results, the difference in the HAMD-24 score between the ATP group and the control group in the fourth week was 8.57 (NCT05431413). Based on the difference in the literature (5.95) between similar drugs (creatine) and the control group in the fourth week,41 we set the difference to 6. According to the pre-experiment results (NCT05431413), the SD of the ATP group was 6.79, the SD of the control group was 7.04 and α was 0.025 on one side. The power was 80%, and the margin of excellence was 1.8. Therefore, 44 subjects were needed in each group. Assuming an attrition of 10%, at least 49 participants are planned to be included in the study. In addition, the difference in the HAMD-24 score between the ATP group and the control group in the second week was 5.49 (NCT05431413). Based on the difference in the literature (5.65) between similar drugs (creatine) and the control group in the fourth week,41 we set the difference to 5.60. According to the pre-experiment results (NCT05431413), the SD of the ATP group was 6.81, the SD of the control group was 7.05, and α was 0.025 on one side. The power was 80%, and the margin of excellence was 1.8. Therefore, 54 subjects were needed in each group. Assuming an attrition of 10%, at least 60 participants are planned to be included.

Therefore, this study will ultimately require 60 participants in each group, with a total of 120 participants.

Recruitment

Patients will primarily be referred by outpatient psychiatrists. During the screening, trained researchers will assess eligibility. The Chinese MINI will be used to verify the DSM-5 MDD criteria and to check for exclusions. Subsequently, vital signs, weight, height, physical exams and ECGs will be recorded.

Randomisation, allocation, concealment and blinding

Eligible MDD individuals will be randomly assigned 1:1 to treatment groups via a blocked randomisation protocol for equal distribution, thus ensuring an equal distribution across the groups. A statistician who is not involved in the study will generate the randomisation code via a blocked randomisation procedure in SPSS, with a block size of six. This statistician will maintain all of the related parameters.

This study will involve blinded drug administrators and non-blinded drug administrators who will manage the drugs.

Non-blinded drug administrators will prepare intravenous drugs for the control group or ATP group corresponding to the subject screening number on a daily basis, according to the randomisation code.

For the ATP group, non-blinded administrators will infuse 10 mL ATP into 100 mL NS and cover the NS label with the subject screening number. For the control group, non-blinded administrators will infuse 10 mL NS into 100 mL NS and cover the NS label with the subject screening number. Non-blinded administrators are responsible for preparing the intravenous drugs.

The blinded drug administrators will then take the prepared interventions from the non-blinded drug administrators and provide intravenous infusions to the participants according to the screening number. Blinded drug administrators are responsible for providing intravenous drugs to the participants.

The blinded drug administrators also provided a 10 mg tab of escitalopram OD.

Participant and rater blinding will be maintained throughout the study.

In the event of serious adverse events (AEs), severe drug interactions or overdose, the principal investigator (PI) will break the blinding scenario by using an emergency envelope to reveal treatment allocation, which will guide subsequent treatments as necessary.

Data collection and management

After enrolment, medical histories will be assembled via the electronic case report form (eCRF). Assessments will be performed with the standardised Chinese versions of the HAMD-24, MARDS, HAMA, BDI, SHAPS, CGI, ISI, SERS and C-SSRS. Moreover, MRI, cognitive function and cytokine analyses will also be performed. Medical records, scale manuals, questionnaires, laboratory/ECG reports and procedure logs will constitute the source data, which will be organised and entered into eCRFs. These will subsequently be reviewed by a quality control team and the PI before being sent to the data manager for format and logic verification. Any issues will be highlighted, and the researcher will be contacted for resolution. Once all of the data are confirmed, the database will be secured and backed up, with file transfers being documented and stored per good clinical practice guidelines.

Statistical analysis

Efficacy will be analysed via an intention-to-treat (ITT) approach. All collected data will be analysed using the Statistical Analysis System (SAS) Statistical Package (V.9.4). Descriptive data will be presented as the means and SDs of normally distributed data and will be presented as medians and IQRs; categorical variables will be presented as frequencies and percentages. The univariate analysis will be performed with parametric tests if the data follow a normal distribution; otherwise, non-parametric tests for efficacy on full analysis datasets (FAS), as well as per protocol datasets (PPS) and safety on safety datasets, will be performed. For the primary outcome measure (HAMD-24 scores), a mixed effects model will be used to evaluate the efficacy of the FAS based on the ITT principle. Moreover, the PPS will be used as a sensitivity analysis for the same statistical analysis. The mixed effects model evaluates the differences in intervention impact on treatment effectiveness over time. A p value <0.05 indicates statistical significance. In addition, Bang’s blinding index will be used to determine whether the blind method was successful in this study.42

Monitoring

Standardised terms categorise the AEs, with their counts and percentages being summarised according to organ class and term. Safety analyses assess risks, thus potentially leading to trial discontinuation for patient protection, based on AE type, frequency and severity.

Discussion

MDD continues to be a major cause of disability worldwide, with current antidepressant therapies demonstrating limitations, including delayed onset of action and suboptimal response rates.4,7 This scenario highlights the urgent need for novel, fast-acting treatments to improve patient outcomes, adherence and quality of life. This RCT seeks to assess the effectiveness of intravenous ATP as an adjunct to escitalopram in treating MDD, thus leveraging the research team’s previous findings on the role of ATP in the neural circuits implicated in depression, particularly the mPFC-LHb pathway.

In many clinical trials, low-dose intravenous infusion of ATP (20–40 mcg/kg/min) has been proved to be safe, so 10 mg each time is relatively safe in this study.43 44 In addition, the strictly controlled 2-week hospitalisation plan can increase compliance and ensure timely attention to the changes in the condition. In case of AEs, early detection, screening and treatment can be carried out to minimise patients’ concerns about treatment. At the same time, being away from the family environment, work pressure and other environmental factors may be conducive to the recovery of MDD.45

Our study is unique in several ways. First, it explores the antidepressant potential of ATP in humans, thus building on preclinical research that has shown that ATP dysregulation is involved in depression pathophysiology25 and that targeting the mPFC-LHb pathway may be related to the alleviation of depressive-like behaviours caused by ATP.39 Although some preliminary clinical trials have hinted at the therapeutic potential of ATP, this study will be the first to rigorously test the effects of ATP in a larger sample of patients with moderate to severe MDD through a randomised, double-blind, controlled design. The combination of clinical scales, cognitive function assessments, advanced neuroimaging techniques (eg, MRI) and biomarkers (eg, cytokines) provides a comprehensive approach to understanding not only the clinical efficacy of this treatment modality but also allows us to assess both short-term and longer-term treatment effects, thus offering insights into the potential for rapid antidepressant action and sustained improvement.

A significant advantage of this study is its systematic approach to data collection and analysis, whereby it will employ robust clinical, neuroimaging and biomarker assessments at multiple time points. This will allow us to assess both short-term and longer-term treatment effects, thus offering insights into the potential for rapid antidepressant effects and sustained improvement. However, despite these strengths, the study has several limitations. The most prominent limitation is the sample size, which may restrict our ability to detect significant differences between the groups. This pilot study, which was designed to evaluate efficacy trends, may not have the statistical power to definitively determine the superiority of ATP over escitalopram monotherapy. Nonetheless, the observed trends will be invaluable in refining future hypotheses and informing the design of larger, fully powered trials. Moreover, the generalisability of our findings may be limited by the specific inclusion and exclusion criteria, which ensure a homogenous study population but may not capture the full spectrum of MDD presentations. For example, the exclusion of patients with comorbid psychiatric disorders or neurological conditions limits the applicability of the findings to patients with more complex clinical profiles, who often present in clinical practice. Another potential limitation is the short duration of the trial, particularly regarding the sustained effects of ATP. Although our 4-week follow-up will provide valuable information about the acute phase of treatment, longer-term studies are needed to assess the durability of the antidepressant effects of ATP.

The rigorous blinding and randomisation procedures in this trial will minimise bias, and the dual-arm design comparing ATP treatment to placebo treatment allows for a clear evaluation of the potential of ATP as an adjunct treatment. In the event of significant positive findings, this study can provide a foundation for ATP to be considered as a viable adjunctive treatment option in MDD, especially in cases wherein rapid symptom relief is desired.

This study represents a novel exploration of ATP as a rapid-acting adjunctive therapy for MDD. Given the limitations of current pharmacotherapies, the potential for ATP to address the urgent need for fast-acting antidepressants is significant. The results of this study will contribute to a deeper understanding of the therapeutic role of ATP and neural mechanisms, thus potentially offering new avenues for the development of innovative depression treatments. As the first-in-human RCT, this study will provide insight into the use of ATP in MDD patients.

Trial status

The recruitment of participants is currently ongoing.

Supplementary material

online supplemental file 1
bmjopen-15-8-s001.docx (30KB, docx)
DOI: 10.1136/bmjopen-2024-098281
online supplemental table 1
bmjopen-15-8-s002.doc (41KB, doc)
DOI: 10.1136/bmjopen-2024-098281

Acknowledgements

We would like to thank all of the staff of Nanfang Hospital who supported the project.

Footnotes

Funding: STI2030-Major Projects (2021ZD0202700, 2022ZD0204700), the National Natural Science Foundation of China (T2394535, 82090032).

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-098281).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Patient and public involvement: Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

References

  • 1.World Health Organization . Depression. Who.int; 2018. [Google Scholar]
  • 2.Walker ER, McGee RE, Druss BG. Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry. 2015;72:334–41. doi: 10.1001/jamapsychiatry.2014.2502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 2018;75:336–46. doi: 10.1001/jamapsychiatry.2017.4602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Kolovos S, van Tulder MW, Cuijpers P, et al. The effect of treatment as usual on major depressive disorder: A meta-analysis. J Affect Disord. 2017;210:72–81. doi: 10.1016/j.jad.2016.12.013. [DOI] [PubMed] [Google Scholar]
  • 5.Morilak DA, Frazer A. Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int J Neuropsychopharmacol. 2004;7:193–218. doi: 10.1017/S1461145704004080. [DOI] [PubMed] [Google Scholar]
  • 6.Gaynes BN, Warden D, Trivedi MH, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60:1439–45. doi: 10.1176/ps.2009.60.11.1439. [DOI] [PubMed] [Google Scholar]
  • 7.Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68 Suppl 8:17–25. [PubMed] [Google Scholar]
  • 8.Bauer M, Pfennig A, Severus E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14:334–85. doi: 10.3109/15622975.2013.804195. [DOI] [PubMed] [Google Scholar]
  • 9.Hansen RA, Gartlehner G, Lohr KN, et al. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med. 2005;143:415–26. doi: 10.7326/0003-4819-143-6-200509200-00006. [DOI] [PubMed] [Google Scholar]
  • 10.Vermeiden M, Kamperman AM, Vulink ME, et al. Early improvement as a predictor of eventual antidepressant treatment response in severely depressed inpatients. Psychopharmacology (Berl) 2015;232:1347–56. doi: 10.1007/s00213-014-3765-1. [DOI] [PubMed] [Google Scholar]
  • 11.Hare BD, Duman RS. Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions. Mol Psychiatry. 2020;25:2742–58. doi: 10.1038/s41380-020-0685-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Liu W-Z, Zhang W-H, Zheng Z-H, et al. Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety. Nat Commun. 2020;11:2221. doi: 10.1038/s41467-020-15920-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Belleau EL, Treadway MT, Pizzagalli DA. The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology. Biol Psychiatry. 2019;85:443–53. doi: 10.1016/j.biopsych.2018.09.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45:1085–98. doi: 10.1016/s0006-3223(99)00041-4. [DOI] [PubMed] [Google Scholar]
  • 15.Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–60. doi: 10.1016/j.neuron.2005.02.014. [DOI] [PubMed] [Google Scholar]
  • 16.Li C-T, Su T-P, Wang S-J, et al. Prefrontal glucose metabolism in medication-resistant major depression. Br J Psychiatry. 2015;206:316–23. doi: 10.1192/bjp.bp.113.140434. [DOI] [PubMed] [Google Scholar]
  • 17.Kimbrell TA, Ketter TA, George MS, et al. Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol Psychiatry. 2002;51:237–52. doi: 10.1016/s0006-3223(01)01216-1. [DOI] [PubMed] [Google Scholar]
  • 18.Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527–44. doi: 10.1016/s0924-977x(02)00102-5. [DOI] [PubMed] [Google Scholar]
  • 19.Kennedy SH, Konarski JZ, Segal ZV, et al. Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. Am J Psychiatry. 2007;164:778–88. doi: 10.1176/ajp.2007.164.5.778. [DOI] [PubMed] [Google Scholar]
  • 20.Lajoie C, Levasseur MA, Paquet N. Complete normalization of severe brain 18F-FDG hypometabolism following electroconvulsive therapy in a major depressive episode. Clin Nucl Med. 2013;38:735–6. doi: 10.1097/RLU.0b013e31829b9bd9. [DOI] [PubMed] [Google Scholar]
  • 21.Tan Z, Liu Y, Xi W, et al. Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nat Commun. 2017;8:13772. doi: 10.1038/ncomms13772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Bowser DN, Khakh BS. ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J Neurosci. 2004;24:8606–20. doi: 10.1523/JNEUROSCI.2660-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lalo U, Palygin O, Rasooli-Nejad S, et al. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 2014;12:e1001747. doi: 10.1371/journal.pbio.1001747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Khakh BS, Gittermann D, Cockayne DA, et al. ATP modulation of excitatory synapses onto interneurons. J Neurosci. 2003;23:7426–37. doi: 10.1523/JNEUROSCI.23-19-07426.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Cao X, Li L-P, Wang Q, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–7. doi: 10.1038/nm.3162. [DOI] [PubMed] [Google Scholar]
  • 26.Xiong W, Cao X, Zeng Y, et al. Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors. J Neurosci. 2019;39:4606–23. doi: 10.1523/JNEUROSCI.3069-18.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.He J-G, Zhou H-Y, Xue S-G, et al. Transcription Factor TWIST1 Integrates Dendritic Remodeling and Chronic Stress to Promote Depressive-like Behaviors. Biol Psychiatry. 2021;89:615–26. doi: 10.1016/j.biopsych.2020.09.003. [DOI] [PubMed] [Google Scholar]
  • 28.Volz HP, Rzanny R, Riehemann S, et al. 31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients. Eur Arch Psychiatry Clin Neurosci. 1998;248:289–95. doi: 10.1007/s004060050052. [DOI] [PubMed] [Google Scholar]
  • 29.Iosifescu DV, Bolo NR, Nierenberg AA, et al. Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder. Biol Psychiatry. 2008;63:1127–34. doi: 10.1016/j.biopsych.2007.11.020. [DOI] [PubMed] [Google Scholar]
  • 30.Forester BP, Harper DG, Jensen JE, et al. 31Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depression. Int J Geriatr Psychiatry. 2009;24:788–97. doi: 10.1002/gps.2230. [DOI] [PubMed] [Google Scholar]
  • 31.Teissier A, Chemiakine A, Inbar B, et al. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors. Cell Rep. 2015;13:1965–76. doi: 10.1016/j.celrep.2015.10.061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Urban DJ, Zhu H, Marcinkiewcz CA, et al. Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology. 2016;41:1404–15. doi: 10.1038/npp.2015.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Li Y, Zhong W, Wang D, et al. Serotonin neurons in the dorsal raphe nucleus encode reward signals. Nat Commun. 2016;7:10503. doi: 10.1038/ncomms10503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Zou W-J, Song Y-L, Wu M-Y, et al. A discrete serotonergic circuit regulates vulnerability to social stress. Nat Commun. 2020;11:4218. doi: 10.1038/s41467-020-18010-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Li B, Piriz J, Mirrione M, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature New Biol. 2011;470:535–9. doi: 10.1038/nature09742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Huang L, Xi Y, Peng Y, et al. A Visual Circuit Related to Habenula Underlies the Antidepressive Effects of Light Therapy. Neuron. 2019;102:128–42. doi: 10.1016/j.neuron.2019.01.037. [DOI] [PubMed] [Google Scholar]
  • 37.Cui Y, Yang Y, Ni Z, et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature New Biol. 2018;554:323–7. doi: 10.1038/nature25752. [DOI] [PubMed] [Google Scholar]
  • 38.Yang Y, Cui Y, Sang K, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature New Biol. 2018;554:317–22. doi: 10.1038/nature25509. [DOI] [PubMed] [Google Scholar]
  • 39.Lin S, Huang L, Luo Z-C, et al. The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway. Biol Psychiatry. 2022;92:179–92. doi: 10.1016/j.biopsych.2022.02.014. [DOI] [PubMed] [Google Scholar]
  • 40.Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med. 2010;152:726–32. doi: 10.7326/0003-4819-152-11-201006010-00232. [DOI] [PubMed] [Google Scholar]
  • 41.Lyoo IK, Yoon S, Kim T-S, et al. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry. 2012;169:937–45. doi: 10.1176/appi.ajp.2012.12010009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Qin Z, Yu Y, Gu H, et al. SAS macro programme for Bang’s Blinding Index to assess and visualise the success of blinding in randomised controlled trials. Gen Psychiatr. 2024;37:e101578. doi: 10.1136/gpsych-2024-101578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Leij-Halfwerk S, Agteresch HJ, Sijens PE, et al. Adenosine triphosphate infusion increases liver energy status in advanced lung cancer patients: an in vivo 31P magnetic resonance spectroscopy study. Hepatology. 2002;35:421–4. doi: 10.1053/jhep.2002.31318. [DOI] [PubMed] [Google Scholar]
  • 44.Agteresch HJ, Dagnelie PC, Rietveld T, et al. Pharmacokinetics of intravenous ATP in cancer patients. Eur J Clin Pharmacol. 2000;56:49–55. doi: 10.1007/s002280050719. [DOI] [PubMed] [Google Scholar]
  • 45.Compton MT, Thompson NJ, Kaslow NJ. Social environment factors associated with suicide attempt among low-income African Americans: the protective role of family relationships and social support. Soc Psychiatry Psychiatr Epidemiol. 2005;40:175–85. doi: 10.1007/s00127-005-0865-6. [DOI] [PubMed] [Google Scholar]

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    Supplementary Materials

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    bmjopen-15-8-s001.docx (30KB, docx)
    DOI: 10.1136/bmjopen-2024-098281
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    bmjopen-15-8-s002.doc (41KB, doc)
    DOI: 10.1136/bmjopen-2024-098281

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