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

NCT00369798 | Completed Phase 1

• 2 other identifiers: 06021506-M-0215
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder; Healthy

Keywords

Unipolar Depression; Phosphorylation; Affinity States; Compartment Analysis; (R)-(11)C Rolipram; Depression; Major Depressive Disorder; MDD; Healthy Volunteer; HV

Outcome Measures

Primary Outcomes (1)

• PET measurement of PDE4 levels.

  3 years

Secondary Outcomes (1)

• Correlation between PDE4 levels and depression symptoms

  3 years

Interventions

PET scan PROCEDURE

Rolipram DRUG

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy Volunteers (n = 70)
• Healthy Control Sample (n = 70): Sixty of these volunteers will have brain PET scans and 10 of these have only blood sampling to compare (R)-\[(11)C\]rolipram levels in artery and vein. 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. Forty of these subjects will have (R)-\[(11)C\]rolipram PET scans with blood sampling and 10 subjects have only blood sampling without PET scan. The healthy volunteers who are used to measure the difference in (R)-\[(11)C\]rolipram concentration between the artery and the vein will not undergo psychiatric assessment because the data will not be compared with those of patients.
• MDD Samples (n = 65)
• MDD Sample-Currently Depressed (n = 65): 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.

You may not qualify if:

• Subjects will be recruited who are drug-na(SqrRoot) 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 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)
• major depression that arose following another major medical or psychiatric condition, and
• prior participation in other research protocols within a year such that radiation exposure would exceed the annual guidelines
• For patients who have two \[C-11\]rolipram PET scans, one before and another after SSRI treatment, previous failures of or intolerance to SSRI may not allow for treatment in the current protocol. In clinical practice, medication can be switched between sertraline and citalopram/escitalopram because sertraline and citalopram/escitalopram have somewhat different therapeutic effects and adverse reactions. Along these lines, we will consider citalopram and its enantiomer escitalopram as being equivalent to each other. Patients will therefore be excluded from the study with two \[C-11\]rolipram PET scans if they previously failed to respond to adequate treatment trials of all medications available for use in the study, or if they have a history of being unable to tolerate all of the study medications. Specifically, patients will be excluded from the study with two \[C-11\]rolipram PET scans if they:
• j) previously proved unresponsive to therapeutic trials of both sertraline and citalopram/escitalopram.
• k) previously developed allergic reactions to both sertraline and citalopram/escitalopram, or discontinued both sertraline and citalopram/escitalopram due to an adverse effect
• l) through any combination of therapeutic unresponsiveness and adverse medication effects, are unsuitable for treatment with both sertraline and citalopram/escitalopram
• m) prolonged QTc in ECG

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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. doi: 10.1111/j.1600-0773.1983.tb03432.x.

  PMID: 6316725 BACKGROUND

• Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci. 1994 Jul;15(7):220-6. doi: 10.1016/0165-6147(94)90315-8.

  PMID: 7940983 BACKGROUND

• 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. doi: 10.1210/edrv-16-3-370. No abstract available.

  PMID: 7671852 BACKGROUND

• Fujita M, Richards EM, Niciu MJ, Ionescu DF, Zoghbi SS, Hong J, Telu S, Hines CS, Pike VW, Zarate CA, Innis RB. cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor. Mol Psychiatry. 2017 May;22(5):754-759. doi: 10.1038/mp.2016.171. Epub 2016 Oct 11.

  PMID: 27725657 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder; Depression

Interventions

Magnetic Resonance Spectroscopy; Rolipram

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Masahiro Fujita, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2006
• First Posted: August 29, 2006
• Study Start: August 2, 2006
• Primary Completion: June 16, 2016
• Study Completion: October 12, 2016
• Last Updated: July 5, 2018

Record last verified: 2016-10-12

Locations

US (1)