Effects of TBS on 5-HT1A receptor binding in treatment resistant depression

Background Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation (rTMS) holds promise as an effective treatment for treatment resistant depression (TRD). rTMS was shown to change brain morphology using magnetic resonance imaging (MRI) and positron emission tomography (PET). Alterations in serotonin-1A receptor expression (5-HT1A) in the brain have been linked to major depression. Moreover, changes in the expression of these receptors - observed after pharmacological treatment, as well as after electroconvulsive therapy - has been linked to antidepressant treatment effects. Objectives of the study Here, our aim is to investigate the effects of iTBS over the left frontal cortex on the 5-HT1A receptor expression in patients with TRD using PET. In addition, effects of iTBS on brain structure and function will be determined using different forms of MRI. Study population 80 patients with TRD who maintain their original medication regimen will be recruited. Study design In this clinical trial 40 patients will receive active iTBS and 40 patients will receive placebo iTBS for treatment duration of two weeks. Before and after two weeks of treatment, patients will be scanned using MRI and PET with the highly specific and selective radiotracer [carbonyl-11C]WAY100635. Follow-up visits will be performed 4, 8 and 12 weeks after treatment for the active iTBS group, respectively. Patients in the placebo iTBS arm will receive active iTBS treatment after the second MRI and PET scan. Relevance and implications of the study This will be the worldwide first study to investigate the effects of iTBS on serotonin-1A receptor expression 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 our knowledge on the serotonergic role in shaping brain morphology, microstructure and structural/functional connectivity. Taken together, our 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.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation (rTMS) holds promise as an effective treatment for treatment resistant depression (TRD). Alterations in serotonin-1A receptor expression in the brain have been linked to major depression. Moreover, changes in the expression of this receptor subtype have been linked to antidepressant treatment effects. Patients with TRD were enrolled into this study and randomized into either an active or sham TBS group. The active group received treatment to the left and right dorsolateral prefrontal cortex (DLPFC) over the course of three weeks. TBS treatment was scheduled at two sessions a day (separated by one hour), five days a week. During each session, intermittent, excitatory TBS (iTBS) was applied to the left DLPFC, while continuous, inhibitory, TBS (cTBS) was performed on the right DLPFC. At baseline and within one week of the end of treatment, patients underwent brain measurements using both positron emission tomography (PET) and different approaches of functional magnetic resonance imaging (rsfMRI) and spectroscopy (MRSI) to investigate changes in functional connectivity and changes in main neurotransmitter levels, respectively. In this clinical trial about half of the patients received active iTBS and half of them received placebo (sham) iTBS for treatment duration. Follow-up visits have been performed 4, 8 and 12 weeks after treatment for the active iTBS group, respectively. Using PET we could show an effect of three-week bilateral TBS treatment on the distribution volumes of the serotonin-1A receptor in a group of patients suffering from TRD, with an increase in serotonin-1A receptor availability correlating with a greater difference in depression score post-treatment. Analysis of fMRI data showed a significant reduction in functional connectivity for patients in the active treatment group between the left stimulation target and the bilateral anterior insula, supporting the role of the salience network in the effects of TMS. Anticorrelations between distinct frontal brain areas, the so called dorsolateral prefontal cortex (DLPFC) and the subgenual cingulate cortex (sgACC), were observed for baseline functional connectivity, corresponding to changes in depression severity, which highlights the importance of this parameter for treatment response. However, in the active treatment group, 53% of the patients responded and 20% remitted, while in the sham treatment group 40% responded, demonstrating a very high placebo effect. We aimed to expand insights in the therapeutic effects of TBS on two major neurotransmitter systems, the inhibitory GABAergic and the excitatory glutamatergic system utilizing MRSI to investigate changes of cortical neurotransmitter levels in patients with TRD. This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.