Official Title: “Treatment-Resistant Depression, Hippocampus Atrophy and Serotonin Genetic Polymorphism”

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.

Study Type: Interventional

Study Design: Treatment, Open Label, Single Group Assignment, Efficacy Study

Study Primary Completion Date: October 2008

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.

We 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 we 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.

Intervention(s) in this Clinical Trial

• Drug: Open label drug treatment
  • Dosage and drug types change based on patients need and response. doxepin, clomipramine, amoxapine, amitriptyline, maprotiline, desipramine, nortriptyline, dexepin, trimipramine, imipramine, protriptyline, isocarboxazid, phenelzine, tranylcypromine, maclobemide, fluvoxamine, paroxetine, fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, atomoxetine, pramipexole, bromocriptine, quetiapine, clozapine, olanzapine, ziprasidone, aripiprazole, paliperidone, Risperidone, bupropion, mitrazapine, pindolol, topiramate, trazodone, Lithium,

Arms, Groups and Cohorts in this Clinical Trial

• 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.

Primary Measures

• Sustained Remission from Depression and Hippocampal Atrophy
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• 5-HT1a Genetic Markers
  • Time Frame: Baseline Visit
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: University of Ottawa

Overall Clinical Trial Officials and Contacts

Pierre M Blier, MD, Ph.D Principal Investigator University of Ottawa Institute of Mental Health Research  

Overall Contact: Chantal Hebert, R.N. 613-722-6521 chantal.hebert@rohcg.on.ca

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00704860

Study ID Number: REB- 200506

ClinicalTrials.gov Identifier: NCT00704860

Health Authority: Canada: Health Canada

University of Ottawa Institute of Mental Health research homepage