Downregulation of Brain Phosphodiesterase Type IV Measured with 11C-(R)-Rolipram Positron Emission Tomography in Major Depressive Disorder

BACKGROUND Phosphodiesterase type IV (PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Basic studies suggest that PDE4 mediates the effects of several antidepressants. This study sought to quantify the binding of 11C-(R)-rolipram, a PDE4 inhibitor, as an indirect measure of this enzyme's activity in the brain of individuals with major depressive disorder (MDD) compared with healthy control subjects. METHODS 11C-(R)-Rolipram brain positron emission tomography scans were performed in 28 unmedicated MDD subjects and 25 age- and gender-matched healthy control subjects. Patients were moderately depressed and about one half were treatment-naive. 11C-(R)-Rolipram binding in the brain was measured using arterial 11C-(R)-rolipram levels to correct for the influence of cerebral blood flow. RESULTS Major depressive disorder subjects showed a widespread, approximately 20% reduction in 11C-(R)-rolipram binding (p = .002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitudes was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms. CONCLUSIONS This study is the first to demonstrate that brain levels of PDE4, a critical enzyme that regulates cAMP, are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD and support the hypothesis that agents such as PDE4 inhibitors, which increase activity within the cAMP cascade, may have antidepressant effects.

[1]  Neural plasticity to stress and antidepressant treatment , 1999, Biological Psychiatry.

[2]  M. Hamilton.  The assessment of anxiety states by rating. , 1959, The British journal of medical psychology.

[3]  Timothy Hagen,et al.  Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety , 2010, Nature Biotechnology.

[4]  V. Pike,et al.  Effects of cAMP‐dependent protein kinase activator and inhibitor on in vivo rolipram binding to phosphodiesterase 4 in conscious rats , 2010, Synapse.

[5]  M. Houslay,et al.  The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. , 1998, Advances in pharmacology.

[6]  J. H. Burn,et al.  ADVANCES IN PHARMACOLOGY , 1957 .

[7]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  M. Åsberg,et al.  A New Depression Scale Designed to be Sensitive to Change , 1979, British Journal of Psychiatry.

[9]  K. Takeda,et al.  Short‐term or long‐term treatments with a phosphodiesterase‐4 (PDE4) inhibitor result in opposing agonist‐induced Ca2+ responses in endothelial cells , 2008, British journal of pharmacology.

[10]  J. O'Donnell,et al.  Phosphodiesterase-4D Knock-Out and RNA Interference-Mediated Knock-Down Enhance Memory and Increase Hippocampal Neurogenesis via Increased cAMP Signaling , 2011, The Journal of Neuroscience.

[11]  S. Kish,et al.  Reduced adenylyl cyclase immunolabeling and activity in postmortem temporal cortex of depressed suicide victims. , 1999, Journal of affective disorders.

[12]  David W. Townsend,et al.  Positon emission tomography: basic science and clinical practice , 2008 .

[13]  A. Willemsen,et al.  Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood-brain barrier. , 2009, The international journal of neuropsychopharmacology.

[14]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[15]  Han-Ting Zhang.  Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. , 2009, Current pharmaceutical design.

[16]  Masahiro Fujita,et al.  Kinetic analysis in human brain of [11C](R)-rolipram, a positron emission tomographic radioligand to image phosphodiesterase 4: A retest study and use of an image-derived input function , 2011, NeuroImage.

[17]  J. Marcusson,et al.  Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims , 1994, Brain Research.

[18]  G. MacQueen,et al.  Increased temporal cortex CREB concentrations and antidepressant treatment in major depression , 1998, The Lancet.

[19]  Jerry L Prince,et al.  Measurement of Radiotracer Concentration in Brain Gray Matter Using Positron Emission Tomography: MRI-Based Correction for Partial Volume Effects , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  R. Duman,et al.  Chronic Antidepressant Administration Increases the Expression of Camp-specific Phosphodiesterase 4a and 4b Isoforms , 1998 .

[21]  N. Harada,et al.  Facilitation of dopaminergic neural transmission does not affect [11C]SCH23390 binding to the striatal D1 dopamine receptors, but the facilitation enhances phosphodiesterase type‐IV activity through D1 receptors: PET studies in the conscious monkey brain , 2001, Synapse.

[22]  W. Fleischhacker,et al.  A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorder. , 1992, Neuropsychobiology.

[23]  P. H. Andersen,et al.  Cyclic AMP phosphodiesterase activity in rat brain following chronic treatment with lithium, imipramine, reserpine, and combinations of lithium with imipramine or reserpine. , 2009, Acta Pharmacologica et Toxicologica.

[24]  Richard E. Carson,et al.  Tracer Kinetic Modeling in PET , 2005 .

[25]  J. O'Donnell,et al.  Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). , 2004, Trends in pharmacological sciences.

[26]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[27]  Yogesh K. Dwivedi,et al.  Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. , 2003, Archives of general psychiatry.

[28]  M. Houslay,et al.  cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. , 1998, The Biochemical journal.

[29]  Yogesh K. Dwivedi,et al.  [(3)H]cAMP binding sites and protein kinase a activity in the prefrontal cortex of suicide victims. , 2002, The American journal of psychiatry.

[30]  J. O'Donnell,et al.  Noradrenergic Activity Differentially Regulates the Expression of Rolipram‐Sensitive, High‐Affinity Cyclic AMP Phosphodiesterase (PDE4) in Rat Brain , 1997, Journal of neurochemistry.