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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 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.

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This study was funded by the Intramural Research Program of the National Institute Mental Health, NIH: projects ZIAMH002852, ZIAMH002793 and ZIAMH002927 under clinical protocol NCT00369798 (06-M-0215). We thank the staff of the Experimental Therapeutics and Pathophysiology Branch for recruitment and clinical care of patients with MDD; the staff of Molecular Imaging Branch for recruitment of healthy control subjects and for performing the PET scans; the staff of NIH’s PET Department (Chief: Peter Herscovitch, MD) for scanning; Wayne C Drevets, MD, for guidance on the design and execution of the study, Dave Luckenbaugh, MA, for assistance for statistical analysis, Ioline Henter, MA, for editorial assistance and PMOD Technologies (Zurich, Switzerland) for providing its image analysis and modeling software.

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Correspondence to M Fujita.

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Dr Zarate is listed as a coinventor 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. The remaining authors declare no conflict of interest.

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Fujita, M., Richards, E., Niciu, M. et al. cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor. Mol Psychiatry 22, 754–759 (2017).

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