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Major Depressive DisorderPhase 1NCT00369798

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

A Phase 1 study testing PET scan and Rolipram in people with Major Depressive Disorder and Healthy, run by National Institute of Mental Health (NIMH) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for
Major Depressive Disorder, Healthy
What is being tested?
PET scan and Rolipram
Type of treatment
Surgery or procedure
How many people
100 participants
Where
1 siteUnited States
Study dates
2 Aug 2006to 12 Oct 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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)
Show all 22Show fewer
  • positive urine drug screen
  • current pregnancy (as documented by pregnancy testing prior to scanning)
  • general MRI exclusion criteria
  • 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:
  • previously proved unresponsive to therapeutic trials of both sertraline and citalopram/escitalopram.
  • previously developed allergic reactions to both sertraline and citalopram/escitalopram, or discontinued both sertraline and citalopram/escitalopram due to an adverse effect
  • through any combination of therapeutic unresponsiveness and adverse medication effects, are unsuitable for treatment with both sertraline and citalopram/escitalopram
  • prolonged QTc in ECG
  • Please note that the exclusion criteria j, k, and l do not apply to patients who have one [C-11]rolipram PET without having antidepressant treatment in this protocol.
  • 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.
  • Please note that these exclusion criteria (with the exception of f and i) do not apply to the healthy volunteers who are used to measure the difference in (R)-[(11)C]rolipram concentration between the artery and the vein, without PET scanning.
  • Subjects beyond age 55 are excluded to reduce the biological heterogeneity encompassed by the MDD criteria, and to reduce the variability of PET data.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Antidepressant Effects on cAMP Specific Phosphodiesterase (PDE 4) in Depressed Patients

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.

Read the 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.

Being tested
PET scan, Rolipram
Keywords
Unipolar Depression, Phosphorylation, Affinity States, Compartment Analysis, (R)-(11)C Rolipram, Depression, Major Depressive Disorder, MDD, Healthy Volunteer, HV
Medical subject headings
Depressive Disorder, Major, Depressive Disorder, Depression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PET scanProcedure or surgery

  • RolipramDrug

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. PET measurement of PDE4 levels.

    Measured: 3 years

Secondary outcomes (1)

  1. Correlation between PDE4 levels and depression symptoms

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Aug 2006 (estimated)
  2. Study start2 Aug 2006
  3. Primary completion16 Jun 2016
  4. Study completion12 Oct 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
100 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00369798
Sponsor's protocol ID
060215
Other IDs
06-M-0215
Status last verified
12 Oct 2016
First submitted
25 Aug 2006
Last updated
5 Jul 2018
Results posted
No

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

    PubMed 6316725

  • 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.

    PubMed 7940983

  • 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.

    PubMed 7671852

  • 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.

    PubMed 27725657

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing PET scan and Rolipram in people with Major Depressive Disorder and Healthy, run by National Institute of Mental Health (NIMH) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

PET measurement of PDE4 levels. (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00369798, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jul 2018.

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