Serotonin Transporter Genetic Variation and Amygdala Responses to Antidepressant Medications in Major Depression

NCT02132286 | Completed Phase 4

• 1 other identifier: D1443L00037
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Major Depressive Disorder

Keywords

Functional magnetic resonance neuroimaging; Serotonin transporter gene polymorphism; Amygdala; Antidepressant; Quetiapine; Citalopram; imaging biomarker

Outcome Measures

Primary Outcomes (1)

• Changes in amygdala responses to negative emotional faces from the pre-treatment baseline to 8 weeks post treatment.

  Consistent with the hypothesis of this study, the primary outcome variable will be the magnitude of Blood Oxygen Level Dependent Responses ( BOLD) within the amygdala as measured by changes in amygdala activation from baseline at week 8 of the treatment in the two treatment groups.

  8 weeks

Secondary Outcomes (1)

• Changes in depression symptom severity as measured by Hamilton Depression Rating Scale from the pre-treatment baseline to week 8 post-treatment

  8 weeks

Other Outcomes (1)

• changes in activity in cingulate and prefrontal regions from the baseline to 8 weeks post treatment

  8 weeks

Study Arms (2)

Quetiapine -XR (extended release)

EXPERIMENTAL

Quetiapine-XR (extended release) 150-300mg- treatment in MDD patients with S/Lg alleles in MDD

Drug: Quetiapine XR (extended release)

Citalopram

ACTIVE COMPARATOR

Citalopram 10-20 mgm/day treatment for 8 weeks in MDD with S/Lg alleles

Drug: Quetiapine XR (extended release)

Interventions

Quetiapine XR (extended release) DRUG

Treatment of quetiapine XR ( extended release)in MDD patients with S/Lg alleles

Also known as: Seroquel XR (extended release)

Citalopram; Quetiapine -XR (extended release)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of Major Depressive Disorder of unipolar subtype by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV) and a score of 18 on the 17-item Hamilton Rating Scale for Depression (HRSD) (Hamilton 1960).
• Both females and males aged 18 to 65 years of Caucasian descent.The association between 5-HTTLPR- s allele and poor response to SSRIs is significant only in Caucasians
• Female patients of childbearing potential must be using a acceptable method of contraception ( contraceptive pill, injection or patch, vaginal ring, intra-uterine device, female condom, contraceptive sponge, diaphragm, cervical cap, lea contraceptive, tubal ligation, natural birth control methods, and withdrawl) and have a negative urine human chorionic gonadotropin (HCG) test at enrolment.
• Able to understand and comply with the requirements of the study 5 All participants should be free of psychotropic medication for a minimum of 4 weeks at recruitment

You may not qualify if:

• Pregnancy or lactation
• Major depression with mood congruent and incongruent psychotic symptoms
• Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
• Known intolerance or lack of response to quetiapine fumarate and citalopram as judged by the investigator
• Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir
• Use of any of the following cytochrome P450 inducers in the 14 days preceding enrolment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids
• Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation
• Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria
• Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 4 weeks prior to enrolment will be excluded. However, patient with occasional use of above mentioned substance but does not fulfil abuse criteria according to DSM-IV during the defined period will be included in the study.
• Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
• Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
• Involvement in the planning and conduct of the study
• Previous enrolment or randomisation of treatment in the present study.
• Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
• A patient with unstable Diabetes Mellitus (DM) 17 Subjects who are contraindicated for MRI (pregnancy, metal implants) will be excluded.

Sponsors & Collaborators

• University of Calgary: lead
• AstraZeneca: collaborator

Study Sites (1)

University of Calgary: Foothills medical centre

Calgary, Alberta, T2N4Z6, Canada

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Rajamannar Ramasubbu, MD, FRCPC.

  University of Calgary

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: May 5, 2014
• First Posted: May 7, 2014
• Study Start: December 1, 2008
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: May 7, 2014

Record last verified: 2014-05

Locations

CA (1)