Serotonin Transporter Genetic Variation and Amygdala Responses to Antidepressant Medications in Major Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

Summary: 
      Major depressive disorder (MDD) is a highly prevalent, chronic and/or recurrent condition
      with substantial morbidity and mortality. It is one of the leading causes of disability
      worldwide. Despite significant advances in pharmacological treatment for depression over the
      last two decades, a significant proportion of patients (10-20%) are resistant to currently
      available treatment. The development of new effective treatment for depression is limited by
      the fact that MDD is a heterogeneous disorder with subgroups based on variations in
      etiological factors and treatment response. Functional magnetic resonance imaging (fMRI)
      approaches offer promise in the prediction and evaluation of clinical response of
      antidepressant treatment.

      Previous fMRI studies have identified increased activity in dorso-lateral prefrontal cortex
      (DLPFC) and decreased amygdala activity from the baseline as imaging markers of
      antidepressant response in patients with MDD. However, these studies have examined MDD as a
      homogenous group without specifying the type of patient group, and brain regions as a priori
      hypothesis.We therefore need studies using combined genetics and neuroimaging measures as
      biomarkers in the prediction and evaluation of clinical response to antidepressants. In this
      study we attempted to determine imaging clinical efficacy markers in previously defined brain
      regions (amygdala and prefrontal regions) for two classes of antidepressants (citalopram and
      quetiapine extended release (XR)) with differential action on serotonin transporter
      inhibition in a subgroup of MDD patients with high risk allele ( S/Lg) of serotonin
      transporter gene polymorphism.
    

Detailed description: 
      Background

      The atypical antipsychotic quetiapine has been found to have significant antidepressant
      action in addition to antipsychotic action. Unlike citalopram a selective serotonin reuptake
      inhibitor (SSRI) quetiapine has no effect on serotonin transporter (5-HTT) but it increases
      post synaptic 5-HT1A binding potentials and down regulates 5-HT2A receptors consistently
      (Tarazi et al., 2002) due to its direct antagonistic effect on 5-HT2A receptors and agonistic
      effect on post synaptic 5-HT1A receptors. The quetiapine induced down regulation of 5-HT2A
      receptors and increased density of 5-HT1A receptors has been attributed to its antidepressant
      effects (Thase et al., 2006). Taking into account that contrary to SSRIs, quetiapine mediated
      antidepressant effect does not depend on 5-HTT inhibition, it is possible that genetic
      factors which regulate 5-HTT expression may have less influence on the outcome of quetiapine
      treatment than on SSRI treatment in depressed patients.

      Rationale for this study

      In this experiment, we proposed to study the efficacy of quetiapine relative to citalopram in
      patients with MDD and high risk serotonin transporter gene polymorphism (5-HTTLPR)S/Lg
      alleles. Since 5-HTTLPR-S/Lg allele confers vulnerability to depression in the context of
      emotional stress (Caspi et al., 2003) and also mediates poor and slower response to SSRI
      antidepressants (Serretti et al., 2007), a study of this nature will have significant
      treatment implications in depressed patients with high risk for stress induced relapses and
      treatment resistance. Given that quetiapine has no affinity for 5-HTT and may normalize the
      receptor changes that occur in conditions with low 5-HTT expression (S and Lg carriers and
      patients with MDD), we predict that compared to citalopram treatment, quetiapine treatment
      will be more effective in reducing amygdala responses to negative stimuli as well as
      depressive symptoms in patients with MDD and high risk S/Lg alleles. It is also predicted
      that because of its direct action on post synaptic 5-HT1A and 5-HT2A receptors, quetiapine
      treatment will show early onset of action on amygdala responses than citalopram treatment
      especially in patients with S allele.

      Primary Hypothesis: There will be a significant decrease in amygdala responses to negative
      facial stimuli in depressed patients with S/Lg allele after short term (1 week) and long term
      (8 weeks) quetiapine treatment compared to citalopram treatment.

      Secondary Hypotheses: The reduction in amygdala responses at week 8 of treatment will
      correlate with clinical improvement, and the reduction in amygdala responses at week one of
      the treatment may predict the subsequent clinical response at week 8.

      Study Objective

      To examine the effects of short term (1 week) and long term (8 weeks) treatment of quetiapine
      150-300 mg and citalopram 10-20 mg on amygdala responses to negative emotional stimuli in
      patients with major depression with high risk alleles (S/Lg)

      Study Plan and Procedures

      This is an eight-week, parallel-group, randomized, double blind comparative trial with a
      repeated measure design in which the patients with major depression will be randomly assigned
      in a 1:1 ratio to receive treatment with either quetiapine 300 mg or citalopram 20mg for an
      8-week period. The subjects will undergo imaging during three separate 60-minute sessions: 1)
      baseline or week 0, 2) one week after initiation of treatment, and 3) 8 weeks after baseline
      or initiation of treatment. Genotyping will be performed in all participants.

      64 Caucasians of both gender with an age range of 20-55 years meeting the criteria of DSM-IV
      (American Psychiatric Association 2000) criteria for major depressive disorder according to
      the Structured Clinical Interview (First et al.,2000) for DSM-IV Axis 1 disorders will be
      recruited from the Calgary Health Region outpatient mental health clinics and through local
      newspaper advertisements. Eligible patients will be randomly assigned in a 1:1 ratio to
      receive either quetiapine or citalopram. Thus each treatment arm will have 32 subjects.

      Clinical assessment and treatment

      At the baseline, Structured Clinical Interview I and II will be performed to determine the
      DSM IV diagnosis of MDD and also to exclude other Axis I psychiatric disorders. Hamilton
      rating scale for depression (HRSD) (will be used to assess the severity of depressive
      symptoms (Hamilton 1960) and Hamilton anxiety rating scale (HAM-A) (Hamilton 1959) will be
      used to rate anxiety symptoms. Additionally, temperament and character inventory (TPI)
      (Cloninger et al 1994) and childhood trauma questionnaire (CTQ) will be administered to
      assess and control for the personality traits such as fear and anxiety and child hood abuse
      that are known to affect amygdala responses to fearful stimuli

      After the baseline assessment and prior to the initiation of treatment, first fMRI session
      will be performed. Then quetiapine XR will be initiated at 50mg/day the first 2 days and 150
      mg/day on day 3 and titrated to 300mg/day by day 4, and citalopram will be initiated at the
      dose of 10 mg /day and titrated to 20 mg/day by day 4. The patients in both treatment arms
      will continue this dosage until the completion of the study protocol 8 weeks later. For the
      patients who could not tolerate or develop adverse effects, the quetiapine dose will be
      reduced to 150 mg/day and citalopram dose will be reduced to 10 mg/day. The patients who
      could not tolerate quetipine 150 mg/day and citalopram 10 mg/day will be terminated from the
      study.During their participation in the study, patients will undergo a clinical assessment at
      week one after the titration of quetiapine and citalopram and a second fMRI session.
      Depressive and anxiety symptoms will be rated using HRSD and HAM-A. Then, patients will be
      evaluated every two weeks and at the week 8 using HRSD and HAM-A. At week 8, a third fMRI
      session will be performed. Adverse effects will be recorded. The patients who could not
      tolerate any of the study medications will be terminated from the study

      Genotyping

      Genotyping of 5-HTTLPR and functional single nucleotide polymorphism (SNP)(A-G) rs 25531 at
      the promoter region will be performed using polymerase chain reaction (PCR) followed by
      double restriction endonuclease digestion as reported previously (Wendland et al., 2006) .
      High resolution agarose gel will be used to determine four alleles: Sa-469 bp (uncut),
      Sg-402+67 bp, La- 512 bp (uncut), and Lg-402+110bp.

      fMRI

      fMRI will be performed on three occasions: i) at the baseline, ii) 1 week after optimizing
      the treatment, iii) 8 weeks after optimization An fMRI block design with presentations of
      angry and fearful facial expressions interleaved with a sensorimotor control task will be
      used to elicit activations in amygdala. This paradigm of perceptual processing of facial
      expressions of negative emotions has been shown to effectively and consistently activate
      amygdala in previous studies (Hariri et al., 2002). The paradigm consists of a total of 6
      runs and during each run, 3 blocks of emotional task interleaved with 4 blocks of
      sensorimotor control task will be presented. During the emotion task, subject will view a
      trio of faces and select one of two faces that expresses the same emotion as the target face
      in the top. Each emotion block will consist of 6 images, three of each gender, and target
      affect (angry and fear). Each facial stimulus will be presented for 5 seconds. The identity
      of all three faces will be always different. During the sensorimotor control task, subjects
      will view a trio of geometric shapes (circles, vertical and horizontal ellipses) and select
      one of two shapes that matches the target shape. Each control block consists of 6 different
      images, and each image will presented for 5 seconds. Accuracy and reaction time will be
      recorded during all scans.

      Method of statistical analysis

      The first level of analysis will be the generation of fMRI maps of brain activity using FMRIB
      Software Library (FSL), a statistical software package specifically designed for fMRI
      applications, which uses the general linear model to compute contrast parameter estimates of
      explanatory variables (in our case, the explanatory variable is face task vs. sensorimotor
      task) for each pixel in the brain images. The result is an estimate of the response magnitude
      in a given pixel that surpasses a specified statistical threshold (typically, p = 0.01).

      The main variable of interest will be the magnitude of activity within the amydala. For each
      patient, regions of interest (ROIs) will be drawn manually to encompass the amygdala within
      each hemisphere with the aid of each patient's anatomical images. Magnitude of activity with
      the ROIs will be recorded. A generalized linear mixed model will be used to analyze group
      data with treatment, and time of session (baseline, 1-week, 8-week) as factors into the
      analysis. As we expect that the sample size of patients with La/La genotype will be smaller
      in each treatment group, the primary analysis will be done only in MDD patients with S/Lg
      alleles to prove our hypothesis. To examine the association between changes in amygdala
      activity and response in depression severity the change in HAM-D for each patient over 8
      weeks will be regressed on the corresponding change in amygdala activity. A similar approach
      will be used to correlate 1-week change in activity with 8-week change in depression
      severity. The other regions that are functionally or structurally connected with amygdala
      such as anterior cingulate region (ACC), dorso-lateral prefrontal cortex (DLPFC),
      dorso-medial prefrontal cortex (DMPFC), and precuneus (PCC) will also be selected for
      exploratory analysis

      The potential confounding factors such as age,sex, childhood adversity and personality index
      of fear and anxiety, baseline depression and anxiety scores will be controlled between the
      groups or will be covaried if there are intergroup differences in these variables.

      Determination of sample size

      As it is expected that approximately 70% of participants will express the S/Lg allele, the
      magnitude of activity within the amygdala is estimated from a meta-analysis by Munafo et al
      (2008). to be 0.10 with a standard deviation of 0.11 Assuming a difference in mean change
      (baseline to 8 weeks) between groups to be 0.05 with a change standard deviation of 0.07, a
      total of 32 patients per group is required to detect this difference with 80% power at a
      two-sided 5% level of significance. A 50% difference in mean change is reasonable based upon
      the results by Sheline et al (2001).
    

Intervention name(s): Quetiapine XR (extended release)
Intervention type(s): Drug
Intervention description(s): Treatment of quetiapine XR ( extended release)in MDD patients with S/Lg alleles
Other intervention name(s): Seroquel XR (extended release)
Intervention MeSH terms: Quetiapine Fumarate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Keywords: Functional magnetic resonance neuroimaging; Serotonin transporter gene polymorphism; Amygdala; Antidepressant; Quetiapine; Citalopram; imaging biomarker