Downregulation of brain phosphodiesterase type IV measured with 11C-(R)-rolipram positron emission tomography in major depressive disorder.
BACKGROUND
Phosphodiesterase type IV (PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Basic studies suggest that PDE4 mediates the effects of several antidepressants. This study sought to quantify the binding of 11C-(R)-rolipram, a PDE4 inhibitor, as an indirect measure of this enzyme's activity in the brain of individuals with major depressive disorder (MDD) compared with healthy control subjects.


METHODS
11C-(R)-Rolipram brain positron emission tomography scans were performed in 28 unmedicated MDD subjects and 25 age- and gender-matched healthy control subjects. Patients were moderately depressed and about one half were treatment-naive. 11C-(R)-Rolipram binding in the brain was measured using arterial 11C-(R)-rolipram levels to correct for the influence of cerebral blood flow.


RESULTS
Major depressive disorder subjects showed a widespread, approximately 20% reduction in 11C-(R)-rolipram binding (p = .002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitudes was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms.


CONCLUSIONS
This study is the first to demonstrate that brain levels of PDE4, a critical enzyme that regulates cAMP, are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD and support the hypothesis that agents such as PDE4 inhibitors, which increase activity within the cAMP cascade, may have antidepressant effects.
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1026, USA. fujitam@mail.nih.gov
Masahiro
M
Fujita
Christina S
CS
Hines
Sami S
SS
Zoghbi
Alan G
AG
Mallinger
Leah P
LP
Dickstein
Jeih-San
JS
Liow
Yi
Y
Zhang
Victor W
VW
Pike
Wayne C
WC
Drevets
Robert B
RB
Innis
Carlos A
CA
Zarate
D000328:Adult; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000097:blood / Q000493:pharmacokinetics; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020889:Rolipram / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D002247:Carbon Isotopes; D026901:Membrane Transport Proteins; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram