Antidepressant Effects on cAMP Specific Phosphodiesterase (PDE4) in Depressed Patients

Phase 1

Completed

• Conditions: Major Depressive Disorder; Healthy

• Registration Number: NCT00369798
• Lead Sponsor: National Institute of Mental Health (NIMH)

Brief 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.

Study Timeline

• Study Start: 2006-08-02
• Study First Submitted: 2006-08-25
• Study First Submitted QC: 2006-08-25
• Study First Posted: 2006-08-29
• Primary Completion: 2016-06-16
• Status Verified: 2016-10-12
• Study Completion: 2016-10-12
• Last Update Submitted: 2018-07-03
• Last Update Posted: 2018-07-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
PET measurement of PDE4 levels.	3 years

Secondary Outcome Measures

Name	Time	Method
Correlation between PDE4 levels and depression symptoms	3 years

Trial Locations

Locations (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike; 🇺🇸 Bethesda, Maryland, United States