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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.

      Key Words

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      Linked Article

      • Evidence for Global Reduction in Brain Cyclic Adenosine Monophosphate Signaling in Depression
        Biological PsychiatryVol. 72Issue 7
        • Preview
          Fujita and coworkers, utilizing 11C-(R)-rolipram positron emission tomography, demonstrate that human subjects with major depression exhibit reductions in the enzyme phosphodiesterase-4 (PDE4) in a number of brain regions (1). PDE4, a cyclic adenosine monophosphate (AMP) phosphodiesterase, is an important regulator of cyclic AMP concentrations in the brain; it has been suggested as a molecular target for antidepressant drug discovery (2). The present study provides support for this premise and also suggests that global reductions in cyclic AMP signaling in the brain may be associated with major depression.
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