Condition category
Mental and Behavioural Disorders
Date applied
07/09/2005
Date assigned
29/09/2005
Last edited
29/09/2006
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Pierre Blier

ORCID ID

Contact details

1145 Carling Avenue
Room LG2043
Ottawa
K1Z 7K4
Canada
+1 613 722 6521 (6908)
pblier@rohcg.on.ca

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

Acronym

Study hypothesis

Tyramine is well known by clinicians for its capacity to increase blood pressure, typically in patients treated with monoamine oxidase inhibitors. The finding that pretreatment with reserpine, which induces a depletion of catecholamines, abolishes the effect of Tyramine on blood pressure suggests that Tyramine acts indirectly as a sympathomimetic agent. It has been shown that Tyramine is taken up in NE neurons by the NE transporter and that by stochiometric displacement, it then releases NE from intraneuronal stores (Hoffman and Lefkowitz 1990). Blood pressure is increased by the release of NE; therefore, blood pressure serves as a simple and reliable index of the action of Tyramine. The Tyramine test (Ghose and Turner 1975) consists of measuring the transient increase in the blood pressure of patients after a Tyramine load. It can be carried out either by determining the dose of Tyramine required to induce a fixed increase in systolic blood pressure (SBP) (for example, 30 mmHg,) or by measuring the effect of a fixed dose of Tyramine. Pretreatment with Tomoxetine (now called Atomoxetine), a relatively potent and selective inhibitor of NE uptake, has been reported to decrease the transient elevation in blood pressure produced by Tyramine administration (Zerbe et al. 1985). In recent work, we have demonstrated that transient blood pressure elevation in response to Tyramine is reduced by pretreating subjects with Desipramine, Nortriptyline, Clomipramine and Reboxetine, three NE uptake inhibitors, but not by pretreating with Paroxetine, a selective 5-HT uptake inhibitor (Blier et al. 1997; Slater et al. 2000; Turcotte et al. 2001). In the proposed study, if treated subjects decrease their pressor response to Tyramine, it will be interpreted as evidence of NE uptake inhibition.
In this study, the 5-HT content of the whole blood will be used as an index of 5-HT uptake in depressed patients and will be measured before and after each week of treatment. Since more than 90% of the 5-HT in the blood is in platelets, it is not necessary to correct this value for the platelet count. Notably, Flament et al. (1987) found that the mean level of 5-HT did not change significantly after 5 weeks of placebo whereas it dropped by 95% after 5 weeks of treatment with clomipramine. In this study, the use of each subject as his own control will allow the use of covariance analysis, increasing the likelihood of detecting a statistically significant difference between the different groups at the end of the treatments.

Ethics approval

Not provided at time of registration

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Condition

Major Depression

Intervention

This is a three-arm, randomized, parallel study designed to assess the inhibition of NE and 5-HT uptake by Venlafaxine, Paroxetine and Atomoxetine. Approximately 40 depressed patients will be randomized to one of three treatment groups with the goal of having at least 10 subjects complete the study in each group. The investigators involved in the Tyramine test or the collecting of biochemical data will be blind to the medications used by patients. This study will be conducted on an outpatient basis.

Intervention type

Drug

Phase

Not Specified

Drug names

Venlafaxine, Paroxetine and Atomoxetine

Primary outcome measures

The primary objective of this study is to find evidence of a dose-dependent inhibition of NE reuptake starting of Venlafaxine at 150 mg/day.

Secondary outcome measures

A secondary objective of this study is to show a lack of effect of Paroxetine on NE reuptake at doses of up to 50 mg/day. Another secondary objective is to show a lack of effect of Atomoxetine on 5-HT reuptake and a similar action of higher doses of Venlafaxine and Atomoxetine on NE reuptake. A third secondary objective is to show a marked effect of Paroxetine and Venlafaxine on 5-HT reuptake starting at low doses.

Overall trial start date

01/08/2004

Overall trial end date

30/04/2005

Reason abandoned

Eligibility

Participant inclusion criteria

1. Male or female patients between 18 and 65 years of age
2. Diagnosis of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatry Association, 1994) using the Structured Clinical Interview for Depression (SCID) (Spitzer 1992)
3. Initial global score 18 on the 17-item Hamilton depression rating scale
4. Written informed consent signed by the patient

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

40

Participant exclusion criteria

1. Evidence of significant physical illness contraindicating the use of Venlafaxine, Paroxetine or Atomoxetine found on physical or in the laboratory data obtained during the first week of the study
2. Evidence of suicidality or severity of depression precluding safe participation in the study
3. Mental retardation (IQ lower than 80) rendering the response to investigators unreliable
4. Pregnancy, or absence of adequate contraceptive method in women with childbearing potential
5. Concurrent use of psychotropic medication such as antipsychotics, mood stabilizers or regular use of high doses of benzodiazepines
6. Lack of response or intolerance to optimal doses of Paroxetine, Venlafaxine or Atomoxetine
7. Participation in another clinical trial within 30 days of entry into the current study

Recruitment start date

01/08/2004

Recruitment end date

30/04/2005

Locations

Countries of recruitment

Canada

Trial participating centre

1145 Carling Avenue
Ottawa
K1Z 7K4
Canada

Sponsor information

Organisation

Wyeth Pharmaceuticals (Canada)

Sponsor details

50 Minthorn Boulevard
Markham
Ontario
L3T 7Y2
Canada

Sponsor type

Industry

Website

http://www.wyeth.com

Funders

Funder type

Industry

Funder name

Wyeth Pharmaceuticals

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes