Dopamine (DA) may play a key role in the pathophysiology of major depressive episode (MDE) and may, in part, mediate the therapeutic action of many antidepressant drugs. Recent animal and human studies suggest that DA transporter (DAT) activity may reflect the general state of DA neurotransmitter activity in the CNS, and alterations in normal DAT activity may reflect alteration in central DA function. A variety of antidepressants affect central DA activity, and this effect is not limited to 'DA-ergic' antidepressants. Studies have shown that repeated administration of antidepressants from all pharmacological classes result in enhanced D2-like receptor binding, and this enhanced sensitization has been suggested as a 'final common pathway' for antidepressant action. [99mTc]TRODAT-1 is a unique SPECT radioligand which is highly selective for the DAT with almost no SERT cross binding. Studies with [99mTc]TRODAT-1 conducted at Penn have shown it to be an effective tool for evaluating alterations in striatal DAT levels. Preliminary studies in patients with Parkinson's disease (compared to healthy controls) have shown [99mTc]TRODAT-1 to be effective for quantifying DAT levels. Preliminary studies from our group have shown a significant increase (12% - 36%) in [99mTc]TRODAT-1 binding to DAT sites in the putamen and caudate regions of patients with MDE compared to controls. We propose to conduct a preliminary study to examine whether increased striatal DAT levels in MDE represent a putative state-dependent biomarker of depression.
For specific aim #1 we will ask: Do increased striatal DA T levels in MDE represent a state-dependent biomarker that is reduced after successful antidepressant treatment? We hypothesize that increased striatal DAT levels in MDE patients will decrease during successful antidepressant treatment, and will not appreciably decrease in patients who do not respond to treatment.
For specific aim #2 we will ask: Do striatal DAT levels remain stable over time in non-depressed, healthy controls? To answer these questions, we will measure striatal DAT levels using [99mTc]TRODAT-1 SPECT with MRI co-localization, before and after 8 weeks of treatment with s-citalopram or placebo in 44 drug-naive MDE patients. We will compare these results to measurements of striatal DAT levels in 22 non-depressed, healthy subjects studied under similar conditions with [99mTc]TRODAT-1 SPECT on two separate occasions 8 weeks apart.
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