Serotonin Transporter Genetic Variation and Amygdala Responses to Quetiapine and Selective Serotonin Reuptake Inhibitor Treatment in Major Depression
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 57
- 试验地点
- 1
- 主要终点
- Changes in amygdala responses to negative emotional faces from the pre-treatment baseline to 8 weeks post treatment.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Pregnancy or lactation
- •Any DSM-IV Axis I disorder not defined in the inclusion criteria.
- •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.
- •Severe claustrophobia
研究组 & 干预措施
Citalopram
Citalopram 10-20 mgm/day treatment for 8 weeks in MDD with S/Lg alleles
干预措施: Quetiapine XR (extended release) (Drug)
Quetiapine -XR (extended release)
Quetiapine-XR (extended release) 150-300mg- treatment in MDD patients with S/Lg alleles in MDD
干预措施: Quetiapine XR (extended release) (Drug)
结局指标
主要结局
Changes in amygdala responses to negative emotional faces from the pre-treatment baseline to 8 weeks post treatment.
时间窗: 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.
次要结局
- Changes in depression symptom severity as measured by Hamilton Depression Rating Scale from the pre-treatment baseline to week 8 post-treatment(8 weeks)
研究者
Rajamannar Ramasubbu
Associate Professor
University of Calgary