Clinical trial NCT04526002: The Utility of Concurrent TBS/fNIRS for Antidepressant Treatment Optimization
Official title: The Utility of Concurrent TBS/fNIRS for Antidepressant Treatment Optimization
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Major Depressive Disorder
Keywords: Theta-Burst Stimulation
Major depression
Treatment prediction
Functional NIRS
Concurrent TBS/fNIRS
Lead sponsor: The Hong Kong Polytechnic University
Sponsor class: OTHER
Collaborators: name: Chinese University of Hong Kong
name: Prince of Wales Hospital, Shatin, Hong Kong
name: Kowloon Hospital, Hong Kong
First posted: 2020-08-25
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients with MDD and healthy controls will undergo TBS/fNIRS to investigate the direct effects of TBS of healthy and presumed neuropathological prefrontal cortex.

This is followed by a 4-week TBS treatment for MDD patients in order to evaluate the relationship between immediate excitability modulations of the DLPFC and treatment response.
Primary purpose: BASIC_SCIENCE

Brief summary: Repetitive transcranial magnetic stimulation (rTMS) with theta bursts (i.e. TBS) of the dorsolateral prefrontal cortex (DLPFC) is an innovative treatment for major depressive disorder (MDD). Indeed, the U. S. Food and Drug Administration (FDA) has only recently approved TBS (in August 2018). However, fewer than 50% of patients show sufficient response to this treatment; markers for response prediction are urgently needed. Moreover, there is a lack of knowledge of the mechanism of action of TBS of the DLPFC. This is due to difficulties of directly measuring prefrontal stimulation effects, as compared to the stimulation of motor cortex and utilizing motor evoked potentials as direct readout. However, knowledge of immediate DLPFC modulation by TBS is necessary to extrapolate downstream effects on the neural and symptoms level.

Thus, there is a need for research that aims to quantify the direct and immediate after-effects of TBS on DLPFC function. Most importantly, with regard to precision medicine, there is a need for research that explores the utility of immediate DLPFC reactivity to TBS for the prediction of antidepressant treatment response. There is common agreement that certain forms of rTMS inhibit or excite brain activity, respectively. However, evidence indicates that there is considerable individual variability in the brain responses to rTMS. Whether differences in individual DLPFC modulation by rTMS can be utilized as a predictive marker for treatment response remains to be investigated.

This research program will exploit the combination of functional near-infrared spectroscopy (fNIRS) with brain stimulation. Concurrent TBS/fNIRS measurements will allow us to systematically investigate TBS-induced modulation of blood oxygenation as a proxy for induced brain activity changes. The findings from this study will (1) elucidate the immediate effects of excitatory and inhibitory TBS on prefrontal activity in TBS treatment-naïve patients with MDD and (2) validate the potential utility of TBS-induced brain modulation at baseline for the prediction of antidepressant response to four weeks of daily TBS treatment.

Major depression is a severe mental disorder and is associated with considerable economic costs but adequate treatments are poorly explored. This research program will pave the way towards an affordable and easy-to-implement method for response prediction before treatment commencement. Thus, our research proposal has high potential to inform tailored treatment strategies, as envisaged in precision medicine.

Detailed description: Please refer to the full proposal

Eligibility criteria: MDD group:

Inclusion Criteria:

* MDD (DSM-5), HAMD17 ≥18, approval for TBS treatment by the physician in charge, stable antidepressive medication 4 weeks before treatment (the sample will include at least 20 drug-naïve patients in order to avoid confounding effects of medication for testing hypothesis 4).

Exclusion Criteria:

* a history of brain surgery, head injury, stroke or neurodegenerative disorder, diagnosis of personality disorder, psychotic features, active suicidal intent, severe somatic comorbidities, cardiac pacemakers, deep brain stimulation, intracranial metallic particles, history of seizures, antiepileptics and benzodiazepines corresponding to a dose of \>1 mg lorazepam/d, substance dependence or abuse, if it is the primary clinical problem.

HC group:

Inclusion Criteria:

* age between 18 and 60, right-handedness.

Exclusion Criteria:

* a current or previous diagnosis of a psychiatric, neurological disorder or severe internal illness, common contraindications to rTMS,26 and a psychiatric disorder in their first-degree relatives.

Primary outcomes:
measure: Response rate after treatment (Montgomery-Asberg depression rating scale, MADRS reduction ≥50% of baseline)
timeFrame: post treatment, up to 22 months
measure: Oxygenated hemoglobin (HbO) change compared to baseline
timeFrame: during and post TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months
Secondary outcomes:
measure: Remission rate after treatment (MADRS≤10)
timeFrame: post treatment, up to 22 months
measure: Absolute change of mean Hamilton depression rating scale (HAMD17) after 2 and 4 weeks of treatment, as well as at 1 month follow-up
timeFrame: at follow-up, up to 30 months
measure: Absolute change of mean Inventory of depression symptomatology-clinician (IDS-C30) after 2 and 4 weeks of treatment, as well as at 1 month follow-up
timeFrame: at follow-up, up to 30 months
measure: Hb change compared to baseline
timeFrame: during and post TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months
measure: the area under curve of HbO and Hb value during stimulation
timeFrame: during TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months
measure: the steepness of the Hb and HbO values change
timeFrame: during TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months
Other outcomes:
measure: Change of Patient Health Questionnaire (PHQ-9, Chinese version) at each treatment day
timeFrame: till to end of treatment, up to 18 months
Locations:
city: Hong Kong
country: Hong Kong
facility: The Hong Kong Polytechnic University
Study officials:
affiliation: The Hong Kong Polytechnic University
name: Georg S Kranz, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kan RLD, Mak ADP, Chan SKW, Zhang BBB, Fong KNK, Kranz GS. Protocol for a prospective open-label clinical trial to investigate the utility of concurrent TBS/fNIRS for antidepressant treatment optimisation. BMJ Open. 2022 Feb 10;12(2):e053896. doi: 10.1136/bmjopen-2021-053896.