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

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ClinicalTrials.gov Identifier: NCT02132286
Recruitment Status : Completed
First Posted : May 7, 2014
Last Update Posted : May 7, 2014
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Rajamannar Ramasubbu, University of Calgary

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.


Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Quetiapine XR (extended release) Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Official Title: Serotonin Transporter Genetic Variation and Amygdala Responses to Quetiapine and Selective Serotonin Reuptake Inhibitor Treatment in Major Depression
Study Start Date : December 2008
Actual Primary Completion Date : April 2012
Actual Study Completion Date : April 2012

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Quetiapine -XR (extended release)
Quetiapine-XR (extended release) 150-300mg- treatment in MDD patients with S/Lg alleles in MDD
Drug: Quetiapine XR (extended release)
Treatment of quetiapine XR ( extended release)in MDD patients with S/Lg alleles
Other Name: Seroquel XR (extended release)

Active Comparator: Citalopram
Citalopram 10-20 mgm/day treatment for 8 weeks in MDD with S/Lg alleles
Drug: Quetiapine XR (extended release)
Treatment of quetiapine XR ( extended release)in MDD patients with S/Lg alleles
Other Name: Seroquel XR (extended release)




Primary Outcome Measures :
  1. Changes in amygdala responses to negative emotional faces from the pre-treatment baseline to 8 weeks post treatment. [ Time Frame: 8 weeks ]
    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.


Secondary Outcome Measures :
  1. Changes in depression symptom severity as measured by Hamilton Depression Rating Scale from the pre-treatment baseline to week 8 post-treatment [ Time Frame: 8 weeks ]
    This clinical efficacy secondary outcome measure is required to correlate with primary measure of amygdala responses to determine whether amygdala changes will be a clinical efficacy surrogate imaging marker.


Other Outcome Measures:
  1. changes in activity in cingulate and prefrontal regions from the baseline to 8 weeks post treatment [ Time Frame: 8 weeks ]
    These regions are functionally connected with amygdala and also have shown changes with antidepressant treatment



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. 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).
  2. 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
  3. 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.
  4. 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

Exclusion Criteria:

  1. Pregnancy or lactation
  2. Any DSM-IV Axis I disorder not defined in the inclusion criteria.
  3. Major depression with mood congruent and incongruent psychotic symptoms
  4. Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
  5. Known intolerance or lack of response to quetiapine fumarate and citalopram as judged by the investigator
  6. 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
  7. 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
  8. Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation
  9. Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria
  10. 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.
  11. Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
  12. Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
  13. Involvement in the planning and conduct of the study
  14. Previous enrolment or randomisation of treatment in the present study.
  15. Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
  16. A patient with unstable Diabetes Mellitus (DM) 17 Subjects who are contraindicated for MRI (pregnancy, metal implants) will be excluded.

18. Severe claustrophobia


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02132286


Locations
Canada, Alberta
University of Calgary: Foothills medical centre
Calgary, Alberta, Canada, T2N4Z6
Sponsors and Collaborators
University of Calgary
AstraZeneca
Investigators
Principal Investigator: Rajamannar Ramasubbu, MD, FRCPC. University of Calgary

Responsible Party: Rajamannar Ramasubbu, Associate Professor, University of Calgary
ClinicalTrials.gov Identifier: NCT02132286     History of Changes
Other Study ID Numbers: D1443L00037
First Posted: May 7, 2014    Key Record Dates
Last Update Posted: May 7, 2014
Last Verified: May 2014

Keywords provided by Rajamannar Ramasubbu, University of Calgary:
Functional magnetic resonance neuroimaging
Serotonin transporter gene polymorphism
Amygdala
Antidepressant
Quetiapine
Citalopram
imaging biomarker

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Citalopram
Quetiapine Fumarate
Serotonin
Dexetimide
Serotonin Uptake Inhibitors
Psychotropic Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists