cAMP Signaling in Brain is Decreased in Unmedicated Depressed Patients and Increased by Treatment with a Selective Serotonin Reuptake Inhibitor

Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using (11)C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after approximately eight weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). (11)C-(R)-rolipram PET scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls. Twenty-three of the 44 patients had a follow-up (11)C-(R)-rolipram PET scan approximately eight weeks after treatment with an SSRI. Patients were moderately depressed (Montgomery-Åsberg Depression Rating Scale=30±6) and about half were treatment-naïve. (11)C-(R)-Rolipram binding was measured using arterial sampling to correct for individual differences in radioligand metabolism. We found in unmedicated MDD patients widespread, ~20% reductions in (11)C-(R)-rolipram binding compared to controls (P=0.001). SSRI treatment significantly increased rolipram binding (12%, P<0.001) with significantly greater increases observed in older patients (P<0.001). Rolipram binding did not correlate with severity of baseline symptoms, and increased rolipram binding during treatment did not correlate with symptom improvement. In brief, consistent with the results of basic studies, PDE4 was decreased in unmedicated MDD patients and increased after SSRI treatment. The lack of correlation between PDE4 binding and depressive symptoms could reflect the heterogeneity of the disease and/or the heterogeneity of the target, given that PDE4 has four subtypes. These results suggest that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effects.