Antidepressant Effects on cAMP Specific Phosphodiesterase (PDE4) in Depressed Patients
Condition: Major Depressive Disorder; Healthy
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      The primary purpose of this protocol is to compare PDE4 levels before and after starting a
      selective serotonin reuptake inhibitor (SSRI) sertraline, citalopram or escitalopram in
      unmedicated depressed patients. The secondary purpose is to compare PDE4 levels between
      unmedicated depressed patients and healthy subjects.
    

Detailed description: 
      Although direct pharmacological effects of antidepressant should manifest rapidly, before
      significant symptom relief appears, typically antidepressant treatment needs to be continued
      for 2 to 4 weeks. This delayed onset of clinical effects indicates involvement of adaptive
      changes in antidepressant effects. Rodent studies have consistently shown upregulation of the
      3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but
      not acute antidepressant treatment including serotonin and norepinephrine uptake inhibitors,
      monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP
      is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by
      cyclic nucleotide phosphodiesterases (PDEs). Type 4 PDE (PDE4) is selective to cAMP in the
      brain. Among components of the cAMP pathway, PDE4 appears to be critical for antidepressant
      effects because an inhibitor of PDE4, 4-[3-(cyclopenotoxyl)-4-methoxyphenyl]-2-pyrrolidone
      (rolipram), showed antidepressant effects both in animals and humans, and various forms of
      antidepressant treatment induced increase in PDE4 in rodents. However, without imaging the
      cAMP pathway before and after antidepressant treatment in depressives, it is not possible to
      study adaptive changes in the signal transduction system and its role in the symptom relief.

      Recently (R)-[(11)C]rolipram has been successfully used to image PDE4 in animals and humans.
      We have confirmed that PDE4 levels can be measured reliably by performing (R)-[(11)C]rolipram
      positron emission tomography (PET) with multiple arterial sampling even in rats. The primary
      purpose of this protocol is to compare PDE4 levels before and after starting a selective
      serotonin reuptake inhibitor (SSRI) sertraline, citalopram or escitalopram in unmedicated
      depressed patients. The secondary purpose is to compare PDE4 levels between unmedicated
      depressed patients and healthy subjects. Baseline scans of patients will be used for this
      second comparison. For the first time, these comparisons have become possible with the new
      PET agent (R)-[(11)C]rolipram. The findings will advance understanding on the role of cAMP
      signal transduction system in the pathology of depression and the mechanisms of
      antidepressant effects.
    

Intervention name(s): PET scan; Rolipram
Intervention type(s): Procedure; Drug
Intervention MeSH terms: Rolipram
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Unipolar Depression; Phosphorylation; Affinity States; Compartment Analysis; (R)-(11)C Rolipram; Depression; Major Depressive Disorder; MDD; Healthy Volunteer; HV