Changes of brain cAMP cascade in major depression measured with ¹¹C-(R)-rolipram PET

Objectives Human postmortem studies indicated that the cAMP cascade is downregulated in major depressive disorder (MDD), and rodent studies showed that antidepressant treatment upregulates the cascade. Brain phosphodiesterase (PDE) 4, which metabolizes the second messenger cAMP has been imaged with ¹¹C-(R)-rolipram. The objectives of this study were to compare ¹¹C-(R)-rolipram binding between MDD patients and healthy controls and also to compare the binding in MDD patients before and after antidepressant.

Methods ¹¹C-(R)-Rolipram PET scans were performed on 24 unmedicated MDD patients and 21 healthy controls. Nine MDD patients repeated a scan 4 - 8 weeks after sertraline or citalopram treatment. To study reproducibility of the measurement, five healthy controls had two scans with intervals of 4-10 weeks. In each voxel, PDE4 levels were measured as V_T/f_P of ¹¹C-(R)-rolipram using Logan plot. Depression and anxiety symptom severity was rated using the Montgomery-Asberg Depression Rating Scale and Hamilton Depression and Anxiety Rating Scales.

Results Unmedicated MDD patients showed 17% lower levels of V_T/f_P than healthy controls in all brain regions (false discovery rate corrected p = 0.031 by SPM without global normalization). There was no significant correlation between the depression or anxiety scores and V_T/f_P. Although the five healthy controls showed retest variability of 6.9% in V_T/f_P, the nine patients who had PET scans before and after treatment showed markedly different V_T/f_P between the two scans with an average absolute difference of 30% ranging from -44% to +110%.

Conclusions Unmedicated patients with MDD showed significantly lower levels of PDE4 than healthy controls, indicating downregulation of the cAMP cascade in depression. The changes after treatment are currently under investigation by studying additional patients