Patient Stratification and Treatment Response Prediction in Neuropharmacotherapy Using Hybrid Positron Emmission Tomography/Magnetic Resconance Imaging (PET/MR)

Selective serotonin reuptake inhibitors (SSRIs) raise serotonin (5-HT) in the synaptic cleft and are the current first line of pharmacological antidepressive treatment. Yet, there is a missing link between this first molecular step in their mechanism of action and observed clinical improvement. We have determined to establish a framework combining genuine molecular and functional imaging, i.e. hybrid pharmaco-PET/MR imaging, of the human serotonergic system in order to predict antidepressant treatment response.

Objectives:

1. To predict antidepressant treatment response from data obtained using hybrid PET/MR with acute pharmacological challenge.
2. To discriminate healthy from depressed subjects using this paradigm.
3. To establish models connecting regional changes in occupancy of serotonin transporters (5-HTT) following citalopram infusion, with changes in brain activation and connectivity of major resting-state hub networks.

Design: Randomized, double-blind, placebo-controlled, cross-over mono-center study.

Materials and methods:

40 major depressed (MDD) and 40 healthy subjects will undergo 2 PET/MR scans on a 3T SIEMENS mMR Biograph scanner: 1. challenge with citalopram 8mg 2. placebo (saline). After structural imaging, functional MRI will be continuously acquired. [11C]DASB will be applied using a bolus + constant infusion paradigm to probe 5-HTT binding potentials and monitor 5-HTT occupancy with drug challenge, applied after 70min, in a single session. Scanning will be terminated 80min after challenge. MDD patients will receive subsequent escitalopram treatment with repeated evaluation of response for 3 months.

Inclusion Criteria:

• General health based on medical history, physical examination and structured clinical interview for DSM-IV (SCID)
• HAM-D≥18 (patients)
• Willingness and competence to sign the informed consent form
• Age 18 to 55 years

Exclusion Criteria:

• Any medical, psychiatric or neurological illness (other than MDD)
• Current or former psychopharmacological treatment
• Current or former substance abuse
• Pregnancy
• Any implant or stainless steel graft or any other contraindications for MRI
• Failure to comply with the study protocol or to follow the instructions of the investigating team
• Participation in studies involving radiation exposure in the past 10 years.
• Body mass index <17 or >30