Antidepressant Effects on cAMP Specific Phosphodiesterase (PDE4) in Depressed Patients - Full Text View

Sponsored by:	National Institute of Mental Health (NIMH)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00369798

Purpose

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.

Condition	Intervention	Phase
Major Depressive Disorder Healthy	Procedure: PET scan Drug: Rolipram	Phase II

MedlinePlus related topics: Antidepressants Depression

Drug Information available for: Rolipram

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Antidepressant Effects on cAMP Specific Phosphodiesterase (PDE 4) in Depressed Patients

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

PET measurement of PDE4 levels. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Correlation between PDE4 levels and depression symptoms [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	50
Study Start Date:	August 2006

Intervention Details:

N/A

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.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Healthy Volunteers (n = 20)

Healthy Control Sample (n = 20): Healthy subjects (ages 18-55) will be selected who have not met criteria for any major psychiatric disorder, have no known first-degree relatives with mood disorders, and have a current score on the Hamilton Depression Rating Scale (HDRS; 17 item) (Williams 1988) in the not depressed range (less than or equal to 7). Control subjects will be matched to depressed subjects for age and gender.

MDD Samples (n = 30)

MDD Sample-Currently Depressed (n = 30): Patients (ages 18-55) will be selected with primary MDD currently depressed by DSM-IV criteria for recurrent MDD and current 17-item HDRS score greater than or equal to 18 or Montgomery-Asberg Depression Rating Scale (MADRS) (Noble et al 1991) greater than or equal to 20 indicating the moderately-to-severely depressed symptoms. All subjects must be physically healthy and aged 18 - 55 years.

EXCLUSION CRITERIA:

Subjects will be recruited who are drug-na ve or who have not received psychotropic drugs for at least 2 weeks (6 weeks for fluoxetine) prior to scanning. Effective medications will not be discontinued for the purposes of the study.

Subjects will also be excluded if they have:

serious suicidal ideation or behavior
psychosis
medical conditions or concomitant medications (see Appendix B) that are likely to influence PET measurement or have significant interactions with sertraline, citalopram or escitalopram.
a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM-IV criteria)
positive urine drug screen
current pregnancy (as documented by pregnancy testing prior to scanning)

f. general MRI exclusion criteria

g. major depression that arose following another major medical or psychiatric condition, and h) prior participation in other research protocols within a year such that radiation exposure would exceed the annual guidelines

Additional exclusion criteria applied to patients who will have antidepressant treatment are:

previously proved unresponsive to a therapeutic trial of sertraline, citalopram or escitalopram.
previously developed allergic reactions to sertraline, citalopram or escitalopram, or discontinued each of these medications due to an adverse effect

Additional exclusion criteria applied to control subjects are:

subjects with a current or past history of other axis I psychiatric conditions
subjects with first-degree family members with current or past history of mood disorder.

Subjects beyond age 55 are excluded to reduce the biological heterogeneity encompassed by the MDD criteria, and to reduce the variability of PET data.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00369798

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Mental Health (NIMH)

More Information

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Andersen PH, Klysner R, Geisler A. Cyclic AMP phosphodiesterase activity in rat brain following chronic treatment with lithium, imipramine, reserpine, and combinations of lithium with imipramine or reserpine. Acta Pharmacol Toxicol (Copenh). 1983 Oct;53(4):337-43.

Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994 Jul;15(7):220-6. Review.

Conti M, Nemoz G, Sette C, Vicini E. Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr Rev. 1995 Jun;16(3):370-89. Review. No abstract available.

Responsible Party:	National Institutes of Health ( Robert B. Innis, M.D./National Institute of Mental Health )
Study ID Numbers:	060215, 06-M-0215
Study First Received:	August 25, 2006
Last Updated:	December 13, 2008
ClinicalTrials.gov Identifier:	NCT00369798
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Unipolar Depression
Phosphorylation
Affinity States
Compartment Analysis
(R)-(11)C rolipram

Depression
Major Depressive Disorder
MDD
Healthy Volunteer
HV

Study placed in the following topic categories:

Rolipram
Depression
Mental Disorders
Mood Disorders

Healthy
Depressive Disorder, Major
Depressive Disorder
Behavioral Symptoms

Additional relevant MeSH terms:

Phosphodiesterase Inhibitors
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses
Psychotropic Drugs

Enzyme Inhibitors
Central Nervous System Agents
Pharmacologic Actions
Antidepressive Agents

ClinicalTrials.gov processed this record on January 30, 2009