cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor

Abstract

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 11C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). 11C-(R)-rolipram positron emission tomographic (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 11C-(R)-rolipram PET scan ~8 weeks after treatment with an SSRI. Patients were moderately depressed (Montgomery-Åsberg Depression Rating Scale=30±6) and about half were treatment naïve. 11C-(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 11C-(R)-rolipram binding compared with 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.

Trial registration: ClinicalTrials.gov NCT00369798.

Conflict of interest statement

Conflict of Interest

Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose.

Figures

Figure 1

11C-(R)-Rolipram binding levels in healthy controls (open symbols) and unmedicated patients with major depressive disorder (MDD, closed symbols) measured as total distribution volume, VT/fP, by unconstrained two-compartment model using brain data in large regions. MDD patients showed a widespread and almost uniform decrease of 17%–21% across 10 brain regions (P=0.001). Mean (95% confidence interval) values across the 10 regions were 13.1 (12.0 – 14.1) and 10.7 (9.8 – 11.6) for healthy controls and unmedicated patients, respectively. Bars indicate group means.

Figure 2

Relationship between age and 11C-(R)-rolipram binding levels before (A) and approximately eight weeks after starting treatment with a selective serotonin uptake inhibitor (SSRI) (B). A significant negative correlation between age and rolipram binding was observed under unmedicated conditions before starting SSRI (P=0.001–0.013, r=0.51–0.63 in 10 areas across brain; A). The significant correlation disappeared after starting SSRIs (P>0.39, r<0.19; B). This finding was due to older patients showing significantly greater increases in rolipram binding after SSRI. The graphs show average data across the 10 large brain regions.