Healthy Clinical Trial
Official title:
Antidepressant Effects on cAMP Specific Phosphodiesterase (PDE 4) in Depressed Patients
The primary purpose of this protocol is to compare PDE4 levels before and after starting a selective serotonin reuptake inhibitor (SSRI) sertraline, citalopram or escitalopram in unmedicated depressed patients. The secondary purpose is to compare PDE4 levels between unmedicated depressed patients and healthy subjects.
Although direct pharmacological effects of antidepressant should manifest rapidly, before
significant symptom relief appears, typically antidepressant treatment needs to be continued
for 2 to 4 weeks. This delayed onset of clinical effects indicates involvement of adaptive
changes in antidepressant effects. Rodent studies have consistently shown upregulation of the
3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but
not acute antidepressant treatment including serotonin and norepinephrine uptake inhibitors,
monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP
is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by
cyclic nucleotide phosphodiesterases (PDEs). Type 4 PDE (PDE4) is selective to cAMP in the
brain. Among components of the cAMP pathway, PDE4 appears to be critical for antidepressant
effects because an inhibitor of PDE4, 4-[3-(cyclopenotoxyl)-4-methoxyphenyl]-2-pyrrolidone
(rolipram), showed antidepressant effects both in animals and humans, and various forms of
antidepressant treatment induced increase in PDE4 in rodents. However, without imaging the
cAMP pathway before and after antidepressant treatment in depressives, it is not possible to
study adaptive changes in the signal transduction system and its role in the symptom relief.
Recently (R)-[(11)C]rolipram has been successfully used to image PDE4 in animals and humans.
We have confirmed that PDE4 levels can be measured reliably by performing (R)-[(11)C]rolipram
positron emission tomography (PET) with multiple arterial sampling even in rats. The primary
purpose of this protocol is to compare PDE4 levels before and after starting a selective
serotonin reuptake inhibitor (SSRI) sertraline, citalopram or escitalopram in unmedicated
depressed patients. The secondary purpose is to compare PDE4 levels between unmedicated
depressed patients and healthy subjects. Baseline scans of patients will be used for this
second comparison. For the first time, these comparisons have become possible with the new
PET agent (R)-[(11)C]rolipram. The findings will advance understanding on the role of cAMP
signal transduction system in the pathology of depression and the mechanisms of
antidepressant effects.
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