Deep Brain Stimulation in Treatment-refractory patients with
Major Depressive Disorder.

BACKGROUND:
Although small previous studies show efficacy of DBS in refractory MDD patients, not much is known about the efficacy or the neurobiological and neuropsychological effects and alterations of brain function during DBS in general or more specifically in MDD.


AIMS & OBJECTIVES:
We aim to investigate clinical efficacy and changes in brain function after deep brain stimulation (DBS) of the nucleus accumbens in 26 patients suffering from refractory MDD.

The main objectives of this study are (1) to assess clinical efficacy of DBS, (2) to assess the effects on D2 receptors binding using SPECT imaging, (3) to assess changes in cerebral perfusion associated with deep brain stimulation (DBS) using fMRI, and to assess changes in neuropsychological functioning over time.


MEASUREMENTS:
Apart form clinical ratings, we will perform repeated SPECT, functional MRI (fMRI) neuroimaging and neuropsychological tests over 18 months of treatment. As control groups for neuroimaging and neuropsychological measures, we will obtain fMRI in 30 healthy controls, and neuropsychological measurements in 30 healthy controls, 30 patients treated with ECT, and 30 chronically depressed patients who are receiving treatment as usual.


DESIGN:
After selection and screening, patients will be implanted bilateral electrodes in the N. Accumbens. After an optimization period of 3 months (if necessary prolonged until 6 months), a double blind cross-over on/off paradigm will be used to investigate clinical efficacy. Furthermore, patients will undergo [123I] IBZM SPECT scanning before surgery, after optimization (month 3-6) and at endpoint at month 18. Functional MRI scans will be obtained at the same timepoints. An additional fourth fMRI-scan will be made after switching the stimulation off (during 1 week after opitimization). During fMRI we will obtain a standard reward task, a face-recognition task and a resting-state scan.

During the study the design has been changed (after approval by the Medical Ethical Committee of the Academic Medical Center). The optimization period had a minimum duration of 3 months and a maximum duration of 12 months (instead of 6 months) to ensure optimal treatment. The Hamiltion Anxiety Scale (HAM-A), Snaith-Hamilton Pleasure Scale (SHAPS), Symptom Checklist 90 (SCL-90), and the additional fourth fMRI-scan 1 week after optimization after switching the stimulation off have been removed from the protocol to reduce patient burden. The protocol is closed with the last follow-up taking place on August 2, 2016.

The primary objective of the present study is to assess efficacy of DBS in the nucleus accumbens for patients with refractory MDD. Secondary objectives are the evaluation of long term efficacy and tolerability of DBS for patients with therapy refractory MDD and its effects on neuropsychological and brain function.



For the additional neuroimaging/neuropsychology part we expect an increase in dopaminergic neurotransmission in SPECT scanning to be related to efficacy of DBS. In fMRI we expect changes in activity within the nodes of the implicated cortical-limbic-thalamic-striatal network.

All measurements are performed both before DBS and after DBS at 5 different timepoints.

Stereotactic implantation of bilateral DBS electrodes in the nucleus accumbens in the DBS group.

After an optimization period of 3 months (if necessary prolonged until 6 months), a double blind cross-over on/off paradigm will be used to investigate clinical efficacy.