Effects of TBS on 5-HT1A Receptor Binding

Effects of Theta-burst Transcranial Magnetic Stimulation on Serotonin-1A Receptor Binding in Treatment Resistant Depression

Background:

Theta-burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS) holds promise as an effective treatment for treatment resistant depression (TRD). rTMS has been linked to neuroplastic changes as shown using magnetic resonance imaging (MRI) and positron emission tomography (PET). Alterations in serotonin-1A receptor expression (5-HT1A) have been linked to major depression. Moreover, changes in 5-HT1A receptor binding - observed after pharmacological treatment, as well as after electroconvulsive therapy - has been linked to neuronal adaptations in response to these antidepressant treatments.

Objectives of the study:

Here, the aim is to investigate the effects of TBS over left and right dorsolateral prefrontal cortex on the 5-HT1A receptor binding in patients with TRD using PET. In addition, effects of iTBS on brain structure and function will be determined using functional, structural and perfusion MRI.

Study population:

80 patients with TRD who maintain their original medication regimen will be recruited.

Study design:

Longitudinal, randomized and double-blind clinical trial. 40 patients will receive active TBS, 40 patients will receive sham TBS for treatment duration of three weeks. Before and after three weeks of treatment, patients will be scanned using MRI and PET with the highly specific and selective radiotracer [carbonyl-11C]WAY100635. A follow-up visit and final examination will be performed 2 and 4 weeks after treatment for the active TBS group, respectively. Patients in the sham TBS arm will receive active TBS treatment immediately after the second MRI and PET scan.

Relevance and implications of the study:

This will be the worldwide first multimodal imaging study to investigate the effects of TBS on serotonin-1A receptor binding in TRD using PET. Thus, the study will add crucial knowledge to the existing literature on the effects of TMS on brain structure and function, related to antidepressant efficacy. Moreover, by combining molecular imaging of serotonergic neurotransmission with structural and functional MRI, the proposed study will increase the investigators knowledge on the serotonergic role in shaping brain morphology, microstructure and structural/functional connectivity. Taken together, the study has the potential to contribute to the development of personalized treatment, the reduction of personal suffering and the reduction of costs and occupational disability.

Study Overview

• Status: Unknown
• Conditions: Treatment Resistant Depression
• Intervention / Treatment: Device: theta-burst stimulation using a MagPro X1000; Device: sham stimulation using a MagPro X1000

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rupert Lanzenberger, MD; Phone Number: +43 40400 35760; Email: rupert.lanzenberger@meduniwien.ac.at
• Study Contact Backup: Name: Georg Kranz, PhD; Phone Number: +43 40400 38250; Email: georg.kranz@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Recruiting
    • Department of Psychiatry and Psychotherapy, Medical University of Vienna
    • Contact: Siegfried Kasper, MD, Prof.; Phone Number: +43-1-40400-3568; Email: sci-biolpsy@meduniwien.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• DSM-5 diagnosis of single or recurrent major depression
• HAMD-17 total score of ≥ 18 and a Clinical Global Impression Scale (CGI-S) of ≥ 4
• Failure of at least two adequate antidepressant treatments
• Age 18-65 years
• Right-handedness (assessed with the Edinburgh Handedness Inventory)

Exclusion Criteria:

• Seizures in medical history
• Lifetime medical history of major systemic illness, neurological disorders and previous brain injuries
• Ferromagnetic implants, cardiac pacemaker, deep brain stimulation and other common MRI exclusion criteria
• Lifetime history of psychotic disorders or current psychotic symptoms
• Substance abuse or dependence within the last 3 months
• Borderline personality disorder (based on DSM-5 criteria)
• Pregnancy
• Active suicidal intent
• Benzodiazepines other than Lorazepam > 2mg/d or any dose of an anticonvulsant
• for participants who participated in an earlier neuroimaging study using ionizing radiation, the total radiation exposure dose of 20 mSv over the last 10 years must not be exceeded, as specified in the legislation on radiation protection.
• failure to comply with the study protocol or to follow the instructions of the investigating team

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: active TBS; 40 patients with TRD will receive active theta-burst stimulation using a MagPro X1000 between the two PET measurements	Device: theta-burst stimulation using a MagPro X1000; TBS over left and right dorsolateral prefrontal cortex for a period of three weeks. iTBS over left DLPFC: 3-pulse 50 Hz bursts will be given every 200ms (at 5 Hz) in 2-second trains with an inter-train interval of 8 seconds. Trains will be repeated 20 to reach a total number of 600 pulses per session. cTBS over right DLPFC: cTBS will comprise uninterrupted bursts to reach a total number of 600 pulses per session. Two sessions per day, separated by 60 minutes; 30 Sessions in total over 3 weeks.; Other Names: repetitive transcranial magnetic stimulation
Sham Comparator: sham TBS; 40 patients with TRD will receive sham stimulation using a MagPro X1000 between the two PET measurements. After the second PET scan they will receive active TBS	Device: sham stimulation using a MagPro X1000; Sham TBS with the coil set at 45° against the skull will be performed over left and right dorsolateral prefrontal cortex for a period of three weeks; Other Names: sham transcranial magnetic stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional 5-HT1A receptor binding	5-HT1A receptor binding using the radioligand [carbonyl-11C]WAY100635	before and after 3 weeks of TBS treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional white matter microstructure using DWI-TBSS	The analysis will be performed using tract-based spatial statistics	before and after 3 weeks of TBS treatment
Regional white matter microstructure using DWI-Tractography	Tractography will be performed	before and after 3 weeks of TBS treatment
Regional grey matter volume using MRI	The analysis will be done using voxel-based morphometry	before and after 3 weeks of TBS treatment
Regional brain perfusion	Regional brain perfusion will be evaluated using Arterial Spin Labeling, ASL	before and after 3 weeks of TBS treatment
Functional connectivity at rest and during tasks	Functional connectivity will be evaluated using resting state and task fMRI	before and after 3 weeks of TBS treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression score using the Hamilton Depression Rating Scale	Depression will be evaluated using the Hamilton Depression Rating Scale	before and after 3 weeks of TBS treatment
Depression score using the Beck Depression Inventory	Depression will be evaluated using the Beck Depression Inventory	before and after 3 weeks of TBS treatment
Global physical activity	assessed using the WHO global physical assessment GPAQ	before and after 3 weeks of TBS treatment

Collaborators and Investigators

• Sponsor: Rupert Lanzenberger
• Investigators: Principal Investigator: Siegfried Kasper, MD, Department of Psychiatry and Psychotherapy, Medical University of Vienna

Publications and helpful links

Helpful Links

• NEUROIMAGING LABs

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Anticipated): November 1, 2019
• Study Completion (Anticipated): November 1, 2019

Study Registration Dates

• First Submitted: June 1, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimate): June 23, 2016

Study Record Updates

• Last Update Posted (Actual): August 16, 2018
• Last Update Submitted That Met QC Criteria: August 14, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depressive Disorder; Depression; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: 1.3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: A database that also includes data from this study will be created