Downregulation of Brain Phosphodiesterase Type IV Measured with 11C-(R)-Rolipram Positron Emission Tomography in Major Depressive Disorder

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Biological psychiatry (Impact Factor: 10.26). 06/2012; 72(7):548-54. DOI: 10.1016/j.biopsych.2012.04.030
Source: PubMed


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 (11)C-(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.
(11)C-(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. (11)C-(R)-Rolipram binding in the brain was measured using arterial (11)C-(R)-rolipram levels to correct for the influence of cerebral blood flow.
Major depressive disorder subjects showed a widespread, approximately 20% reduction in (11)C-(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.
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.

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    • "Enzymes in the PDE4 family catalyze the hydrolysis of cyclic AMP (cAMP) and have a critical role in controlling the intracellular concentration of cAMP and increasing phosphorylation of cAMP-response element-binding protein (Li et al, 2009). PDE4s are found throughout the brain (Perez-Torres et al, 2000), but their levels are decreased in unmedicated depressed individuals (Fujita et al, 2012). This reflects a downregulation of the cAMP cascade that can potentially be restored using PDE4 inhibitors (Duman et al, 1999), an idea which is supported by an increasing number of animal studies that indicate the potential of PDE4 inhibitors for novel treatments of anxiety and depression (Halene and Siegel, 2007; Li et al, 2009). "
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    • "The greater number of samples may also explain the marginally more accurate results obtained with IDIF compared to PBIF (Table 5). Finally, using both PBIF and IDIF, we were able to demonstrate a widespread decrease in [ 11 C](R)-rolipram binding in depressed patients as compared to healthy subjects, proving that the clinical results obtained with full arterial input function (Fujita et al., 2012) can be obtained using either technique. "
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