Secondary Research Project: Monoamine Transporter Occupancy

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Until now, determining whether patients were receiving an adequate dose of a given antidepressant medication was based almost exclusively upon the experience of the prescribing physician. Recently in vivo imaging technology with PET (positron emission tomography) and SPECT (single photon emission computed tomography) are emerging as new tools for assessment and optimization of pharmacological treatment (e.g. monitor adequacy of dosing), psychiatric medication development, and basic understanding of the pathophysiology of psychiatric illness. However, these techniques are associated with limited availability and significant financial costs that preclude the availability of this technology to the vast majority of clinicians. The goal of this project is to provide a valid and simpler alternative (an assay using a human blood sample) to PET imaging to furnish similar in vivo molecular site occupancy data. Briefly, it now appears that most SSRI antidepressants block approximately 80% of their target serotonin transporters (SERT) at standard clinical doses. This data suggests that appropriate clinical dosing might best be determined by assessing brain SERT occupancy. We have developed a unique method in which we are able to measure the magnitude of 5-HT, NE or dopamine (DA) transporter occupancy in antidepressanttreated patients by exposing cells transfected with the human SERT, NET or DAT to the patients' serum after steady-state is attained. Following validation of this technique using concomitant PET imaging we will determine what magnitude of serotonin and/or norepinephrine uptake blockade is required for an optimal treatment response. Simply stated, if a patient has not responded to a standard dose of an SSRI or SNRI, is it because they have not yet achieved a substantial occupancy of the SERT and/or norepinephrine (NET) transporter? These data may be extremely valuable in monitoring patient compliance, the need for dosage adjustment and, in the case of adequate occupancy without therapeutic response, information that provides a rational decision to switch medication class or initiate other treatment options.