Olfactory and Brain Stimulations in Treatment-resistant Depression

Official title

Combining Hedonic Olfactory and BRAin Stimulations in Treatment-resistant Depression

Overview

This is a prospective, randomized, double-blind, parallel-group controlled trial. The aim of this research project is to compare the clinical benefits achieved in patients with major depressive disorder (MDD) following two types of intervention: iTBS active alone or iTBS active combined with olfactory stimulations.

Detailed description

Major depressive disorder (MDD) is the most widespread psychiatric disorder, affecting 5% of adults according to the World Health Organization. Anhedonia, defined as the loss of the ability to experience pleasure, is one of the key symptoms of depression, possibly due to a dysfunction of the reward system. Intermittent theta-burst stimulation (iTBS) targeting the dorsolateral prefrontal cortex (DLPFC) has been demonstrated as an emerging treatment option for treatment-resistant depression. One explanation is that iTBS could work through modulating the reward system (increasing dopamine release). One way to improve the therapeutic benefits of non-invasive brain stimulation is to combine it with other therapeutic strategies. Interestingly, olfactory training -daily short-term exposure to pleasant odors- improves significantly depressive symptoms in MDD patients. Indeed, the olfactory system and the reward system are closely related through the olfactory tubercle, which is in the ventral striatum and directly connected to the ventral tegmental area.

The general aim of this research project is to test whether a combination of iTBS targeting the left DLPFC with an olfactory training can improve treatment outcome in MDD, compared to iTBS targeting the left DLPFC alone.

The investigators hypothesize that combining iTBS treatment on DLPFC with hedonic olfactory stimulation potentiates the effect of iTBS treatment administered alone on depressive symptoms, especially anhedonia (physical, social or olfactory). Moreover, the investigators also hypothesize that the superiority of the combined approach is underpinned by greater modulation of connectivity activity and strength between brain regions involved in dopaminergic transmission, compared with iTBS alone.

Interventions

• Device Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) combined with pleasant odors delivered during the iTBS procol.
  Device: MagPro X100 (MagVenture, Mag2Health, France) iTBS protocol targeting the left dorsolateral prefrontal cortex: 50 consecutive sessions allocated on 10 days (i.e., 5 sessions per working day, 1 hour apart, for 2 weeks). One iTBS session: burst of 3 pulses at 50 Hz repeated at 200 ms intervals for 2 s (i.e., at 5 Hz) at an intensity of 90% of rMT. A 2 s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. Pleasant odorants will be delivered using passive diffu
• Device Non-invasive brain stimulation protocol (intermittent theta burst protocol (iTBS)) delivered alone.
  Device: MagPro X100 (MagVenture, Mag2Health, France) iTBS protocol targeting the left dorsolateral prefrontal cortex: 50 consecutive sessions allocated on 10 days (i.e., 5 sessions per working day, 1 hour apart, for 2 weeks). One iTBS session: burst of 3 pulses at 50 Hz repeated at 200 ms intervals for 2 s (i.e., at 5 Hz) at an intensity of 90% of rMT. A 2 s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session.

Primary outcome measures

• Change in MADRS score before and after intervention to characterized the number of depressed patients who reach remission criteria (MADRS ≤ 10) in each group [Time frame: 4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.]

Secondary outcome measures (8)

• Group differences in Montgomery-Asberg Depression Rating Scale (MADRS) score changes [Time frame: 4 times : Before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.]
• Group differences in Beck Depressive Inventory (BDI) score changes [Time frame: 4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.]
• Group differences in European Test of Olfactory Capabilities (ETOC) score changes [Time frame: 2 times : Before the Intervention (J0), immediately following the end of the Intervention (J15)]
• Group differences in the Chapman Social Anhedonia Scale (SAS) [Time frame: 4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.]
• the Chapman Physical Anhedonia Scale (PAS) score changes [Time frame: 4 times : before the Intervention (J0), immediately following the end of the Intervention (J15), 1 (M1) and 3 months (M3) after the end of the Intervention.]
• Group differences in conditioned motor evoked potential (MEP) peak-to-peak amplitude changes [Time frame: 2 times : before the Intervention (J0), immediately following the end of the Intervention (J15)]
• Group differences in functional connectivity changes in the targeted brain network [Time frame: 2 times : before the Intervention (J0), immediately following the end of the Intervention (J15)]
• Group differences in the Childhood Trauma Questionnaire (CTQ) score changes [Time frame: 1 time : Before the Intervention (J0)]

Eligibility criteria

Inclusion criteria

• had a primary diagnosis of single-episode or recurrent non-psychotic major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria;
• scored 20 or over on the MADRS (Montgomery-Åsberg Depression Rating Scale) (Montgomery and Åsberg, 1979) and scored higher than 2 on the MADRS item 8 anhedonia factor score;
• a stable antidepressant medication for 4 weeks prior to inclusion; be able to speak and read French;
• sign a consent form before intervention.

Exclusion criteria

• a pre-existing condition that affects olfaction including congenital anosmia, upper respiratory tract infection, nasal and/or sinus disease, brain injury or nasal surgery; a neurological disease;
• other comorbid psychiatric disorders or substance abuse (except tobacco);
• contraindications to TMS (medical devices implanted or metallic foreign body in the head);
• pregnant or lactating mothers (controlled by urine pregnancy tests);
• measure of protection or guardianship of justice.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

France · 1 center

• CH Le Vinatier — Bron

Publications

• Imbert L, Neige C, Dumas M, Bensafi M, Mandairon N, Brunelin J. 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. PMID 39744036

Identifiers

NCT: NCT05661383 · 2022-A01967-36

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗