Treatment-Resistant Depression, Hippocampus Atrophy and Serotonin Genetic Polymorphism
Condition: Major Depression
MeSH terms: Atrophy; Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

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.
    

Intervention name(s): Open label pharmacotherapy
Intervention type(s): Other
Intervention description(s): 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 intervention name(s): All classes of antidepressants, based on patient need
Intervention MeSH terms: Antidepressive Agents
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: healthy volunteers treatment resistant major depression hippocampus atrophy MRI serotonin genotyping