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

Mol Psychiatry. 2017 May;22(5):754-759. doi: 10.1038/mp.2016.171. Epub 2016 Oct 11.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Adult
  • Antidepressive Agents / therapeutic use
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Brain / metabolism*
  • Carbon Radioisotopes
  • Case-Control Studies
  • Cyclic AMP / metabolism*
  • Depression / diagnostic imaging
  • Depression / drug therapy*
  • Depression / metabolism*
  • Depressive Disorder, Major / diagnostic imaging
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics
  • Positron-Emission Tomography / methods
  • Rolipram / pharmacokinetics
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Signal Transduction / drug effects

Substances

  • Antidepressive Agents
  • Carbon Radioisotopes
  • Phosphodiesterase 4 Inhibitors
  • Serotonin Uptake Inhibitors
  • Cyclic AMP
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Rolipram

Associated data

  • ClinicalTrials.gov/NCT00369798