Treatment-Resistant Depression, Hippocampus Atrophy and Serotonin Genetic Polymorphism - Full Text View

Sponsor:	University of Ottawa
Information provided by:	University of Ottawa
ClinicalTrials.gov Identifier:	NCT00704860

Purpose

Reduction of volume of the hippocampus has been associated with major depression in many studies. It has been suggested that antidepressants may protect against hippocampus volume loss in humans associated with multiple episodes of depression and may also reverse the reduction of volume caused by the depression. In addition, genetic markers for serotonin are implicated with depression, and may be an indication of reduced response to antidepressant treatments.

This study aims to enroll patients who are defined as having treatment resistant depression (no remission after at least 2 treatments trials with an antidepressant). They will receive an MRI scan at the initial visit and either 6 months after sustained remission or 12 months after they enter the study for non-remitters. They will also be asked to give a blood sample for genotyping. They will be matched by age and handedness to healthy volunteers with no personal history of depression who will also receive an MRI scan and genotyping.

The first aim is to compare hippocampal volume of depressed subjects to healthy controls. It is anticipated that subjects will initially have smaller hippocampal volume but of those who sustain remission, there will be a small increase in hippocampal volume. It is also anticipated that specific genetic markers will be related to individuals response to antidepressant treatments.

Condition	Intervention	Phase
Major Depression	Other: Open label pharmacotherapy	Phase IV

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Treatment-Resistant Depression, Hippocampus Atrophy and Serotonin Genetic Polymorphism

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Antidepressants Depression

Drug Information available for: Serotonin

U.S. FDA Resources

Further study details as provided by University of Ottawa:

Primary Outcome Measures:

Sustained Remission from Depression and Hippocampal Atrophy [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

5-HT1a Genetic Markers [ Time Frame: Baseline Visit ] [ Designated as safety issue: No ]

Enrollment:	27
Study Start Date:	February 2005
Study Completion Date:	December 2010
Primary Completion Date:	November 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: TR TR- Subjects defined as having treatment resistant depression, who have failed at least 2 adequate trials of an antidepressant. Subjects will be treated in an open label trial for their depression, with the goal of sustained remission.	Other: Open label pharmacotherapy Dosage and drug types change based on patients need and response. doxepin, clomipramine, amoxapine, amitriptyline, maprotiline, desipramine, nortriptyline, trimipramine, imipramine, protriptyline, isocarboxazid, phenelzine, tranylcypromine, moclobemide, fluvoxamine, paroxetine, fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, atomoxetine, pramipexole, bromocriptine, quetiapine, clozapine, olanzapine, ziprasidone, aripiprazole, paliperidone, Risperidone, bupropion, mirtazapine, pindolol, topiramate, trazodone, Lithium, Other Name: All classes of antidepressants, based on patient need

Arms

Assigned Interventions

Experimental: TR

TR- Subjects defined as having treatment resistant depression, who have failed at least 2 adequate trials of an antidepressant. Subjects will be treated in an open label trial for their depression, with the goal of sustained remission.

Other: Open label pharmacotherapy

Dosage and drug types change based on patients need and response.

doxepin, clomipramine, amoxapine, amitriptyline, maprotiline, desipramine, nortriptyline, trimipramine, imipramine, protriptyline, isocarboxazid, phenelzine, tranylcypromine, moclobemide, fluvoxamine, paroxetine, fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, atomoxetine, pramipexole, bromocriptine, quetiapine, clozapine, olanzapine, ziprasidone, aripiprazole, paliperidone, Risperidone, bupropion, mirtazapine, pindolol, topiramate, trazodone, Lithium,

Other Name: All classes of antidepressants, based on patient need

Detailed Description:

Individuals who are defined as having treatment-resistant major depression (failure of at least 2 trials of an antidepressant at an adequate dose) and currently meet DSM-IV criteria for depression qualify for this study. At the initial visit, each subject is given an MRI in order to perform a volumetric analysis of their hippocampus and a blood sample is taken in order to determine their genotype for the 5-HT1a(serotonin) promoter. Each patient is then aggressively treated (open label) for depression with the goal of remission. A second MRI scan is completed 6 months after sustained remission or 12 months from baseline if remission is not met or sustained.

The investigators will select healthy volunteer controls with no personal or first relative history of depression and match with the subjects based on age and handedness. Genotyping and and MRI scan will be performed on the healthy subjects in order to compare all parameters.

Hypothesis: It is anticipated that the hippocampal volume will be smaller than those of matched controls. It is also anticipated that the Homozygous G(-1019) genotype will be more prevalent in the patient group than in the healthy subjects.

In addition, it is hypothesized that the investigators should find a small increase in hippocampal volume after long-term treatment. Also, most non-responders will be of homozygous G(-1019) 5-HT1a genotype and will have the greatest degree of hippocampal atrophy. Moreover, it is hypothesized that patients carrying a long allele of 5-HTTLPR polymorphism for 5-HTT might show a better response to antidepressants in general. Finally, it is anticipated that the TPH*A variant of the gene coding for tryptophan hydroxylase will be associated with poorer outcome.

Eligibility

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

Criteria

Inclusion Criteria:

Male or female between ages of 18 to 65 years of age.
A diagnosis of Major Depression according to the DSM-IV criteria
Failing to achieve remission while receiving at least two different antidepressants at adequate dosage for at least 6 weeks.
Initial score of at least 18 on the HAMD-17 item rating scale

Exclusion Criteria:

A diagnosis of substance abuse or dependence in the last 6 months or a lifetime diagnosis of substance abuse according to the DSM-IV criteria, elicited by inquiry.
A diagnosis of post-traumatic stress disorder, schizophrenia, schizo-affective disorder and other psychotic disorders, anorexia nervosa or a history of a manic or mixed episode
Major medical illnesses including endocrine and neurological disorders, as well as a history of significant head trauma
Exposure to oral or intravenous steroids
Contraindications to magnetic resonance imaging
An IQ less than 80

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00704860

Locations

Canada, Ontario
University of Ottawa Institute of Mental Health Research
Ottawa, Ontario, Canada, K1Z 7K4

Sponsors and Collaborators

University of Ottawa

Investigators

Principal Investigator:

Pierre M Blier, MD, Ph.D

University of Ottawa Institute of Mental Health Research

More Information

Additional Information:

University of Ottawa Institute of Mental Health research homepage This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Pierre Blier, MD, Ph.D., University of Ottawa Institute of Mental Health Research
ClinicalTrials.gov Identifier:	NCT00704860 History of Changes
Other Study ID Numbers:	REB- 200506
Study First Received:	June 18, 2008
Last Updated:	January 18, 2011
Health Authority:	Canada: Health Canada

Keywords provided by University of Ottawa:

healthy volunteers treatment resistant major depression hippocampus atrophy MRI serotonin genotyping

Additional relevant MeSH terms:

Depression
Depressive Disorder
Depressive Disorder, Major
Atrophy
Behavioral Symptoms
Mood Disorders
Mental Disorders
Pathological Conditions, Anatomical
Antidepressive Agents
Serotonin

Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 12, 2012