Combining pleasant Olfactory and BRAin stimulations in treatment-resistant depression (COBRA): study protocol for a randomized controlled trial

Laetitia Imbert; Cécilia Neige; Maylis Dumas; Moustafa Bensafi; Nathalie Mandairon; Jérôme Brunelin

doi:10.3389/fpsyg.2024.1451096

Combining pleasant Olfactory and BRAin stimulations in treatment-resistant depression (COBRA): study protocol for a randomized controlled trial

Front Psychol. 2024 Dec 17:15:1451096. doi: 10.3389/fpsyg.2024.1451096. eCollection 2024.

Authors

Laetitia Imbert^{1

2}, Cécilia Neige^{1

2}, Maylis Dumas^{1

2}, Moustafa Bensafi³, Nathalie Mandairon³, Jérôme Brunelin^{1

2}

Affiliations

¹ Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Neurosciences de Lyon U1028 UMR5292, PSYR2, Bron, France.
² Le Vinatier, Psychiatrie Universitaire Lyon Métropole, Bron, France.
³ Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Neurosciences de Lyon U1028 UMR5292, NEUROPOP, Bron, France.

Abstract

Background: Anhedonia, including social, physical, and less-known, olfactory, stands as a core symptom of major depressive disorder (MDD). At the neurobiological level, anhedonia has been associated with abnormal activity within the reward system, suggesting a key role for dopamine. Repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as an innovative treatment for alleviating depressive symptoms. Stimulation of the dorsolateral prefrontal cortex (DLPFC) has been shown to both improve anhedonia and induce dopamine release. Moreover, research suggests that the efficacy of rTMS is improved when applied to an activated brain network rather than at rest. Our goal is to induce a dual activation of the reward system using a combined rTMS protocol and an intervention based on pleasant odorant exposure known to stimulate this system.

Methods: In this randomized controlled trial, we propose to combine rTMS targeting the left DLPFC with pleasant odorant stimulation to alleviate depressive symptoms. A total of 80 patients with treatment-resistant MDD will be randomly assigned to two groups and will receive 50 sessions of either: 1- rTMS and hedonic olfactory stimulations, or 2- rTMS alone. We will conduct pre- and post-assessments measuring depression severity, physical, social, and olfactory anhedonia, as well as the connectivity and activity of brain regions involved in the pathophysiology of depression and the reward circuitry.

Discussion: This study may strengthen the development of more effective rTMS interventions and pave the way for the establishment of rTMS combined with olfactory training as a safe, effective, and easily accessible treatment for MDD patients. In addition, this study will contribute to a better understanding of the mechanisms and physiopathology of MDD.

Trial registration number: #NCT05661383.

Keywords: dorsolateral prefrontal cortex (DLPFC); major depressive disorder (MDD); olfaction; repetitive transcranial magnetic stimulation (rTMS); reward system.

Associated data

ClinicalTrials.gov/NCT05661383

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Fondation de France #00123049/WB-2021-35902 (JB and NM), the Agence Nationale de la Recherche (ANR) #AAPG 2023-CE17-COBRA (JB and NM), the Fondation Pierre Deniker (CN), and the Congrès Français de Psychiatrie (MD). The sponsor of the study played no role in the design of this study and no role during its execution, analyses, interpretation of the data, or decision to submit results. The funder of the study had no role in study design, data collection, data interpretation, or writing of the report.