Major Depressive Disorder Clinical Trial
Official title:
Serotonin Transporter Genetic Variation and Amygdala Responses to Quetiapine and Selective Serotonin Reuptake Inhibitor Treatment in Major Depression
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.
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).
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT05537558 -
Precision Medicine for the Prediction of Treatment (PROMPT) Response (PROMPT)
|
||
Terminated |
NCT02192099 -
Open Label Extension for GLYX13-C-202, NCT01684163
|
Phase 2 | |
Completed |
NCT03142919 -
Lipopolysaccharide (LPS) Challenge in Depression
|
Phase 2 | |
Recruiting |
NCT05547035 -
Identification of Physiological Data by a Wearable Monitor in Subjects Suffering From Major Depression Disorders
|
N/A | |
Terminated |
NCT02940769 -
Neurobiological Effects of Light on MDD
|
N/A | |
Recruiting |
NCT05892744 -
Establishing Multimodal Brain Biomarkers for Treatment Selection in Depression
|
Phase 4 | |
Recruiting |
NCT05537584 -
SMART Trial to Predict Anhedonia Response to Antidepressant Treatment
|
Phase 4 | |
Active, not recruiting |
NCT05061706 -
Multicenter Study of Lumateperone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder
|
Phase 3 | |
Completed |
NCT04479852 -
A Study of the Safety and Efficacy of SP-624 in the Treatment of Adults With Major Depressive Disorder
|
Phase 2 | |
Recruiting |
NCT04032301 -
Repeated Ketamine Infusions for Comorbid PTSD and MDD in Veterans
|
Phase 1 | |
Recruiting |
NCT05527951 -
Enhanced Measurement-Based Care Effectiveness for Depression (EMBED) Study
|
N/A | |
Completed |
NCT03511599 -
Cycloserine rTMS Plasticity Augmentation in Depression
|
Phase 1 | |
Recruiting |
NCT04392947 -
Treatment of Major Depressive Disorder With Bilateral Theta Burst Stimulation
|
N/A | |
Recruiting |
NCT05895747 -
5-HTP and Creatine for Depression R33 Phase
|
Phase 2 | |
Recruiting |
NCT05273996 -
Predictors of Cognitive Outcomes in Geriatric Depression
|
Phase 4 | |
Recruiting |
NCT05813093 -
Interleaved TMS-fMRI in Ultra-treatment Resistant Depression
|
N/A | |
Recruiting |
NCT05135897 -
The Neurobiological Fundaments of Depression and Its Relief Through Neurostimulation Treatments
|
||
Enrolling by invitation |
NCT04509102 -
Psychostimulant Augmentation of Repetitive TMS for the Treatment of Major Depressive Disorder
|
Early Phase 1 | |
Recruiting |
NCT06145594 -
EMA-Guided Maintenance TMS for Depression
|
N/A | |
Recruiting |
NCT06026917 -
Assessing Dopamine Transporter Occupancy in the Patients With Depression Brain With Toludesvenlafaxine Hydrochloride Extended-Release Tablets Using 11C-CFT Positron Emission Tomography (PET)
|
Phase 4 |