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Neurobiological Mechanisms of Pathological Rumination and Effects of Aripiprazole
Condition(s) studied
Major Depressive Disorder (MDD)Rumination
Investigational drug(s) / intervention(s)
EscitalopramAripiprazole 5mg
Escitalopram: Escitalopram will be administered orally at a fixed dose of 20 mg/day for 8 weeks. This SSRI antidepressant is used as baseline pharmacological treatment for patients with major depressive disorder (MDD), either as monotherapy or in combination with aripiprazole. No other psychotropic medications are allowed during the study period.
Aripiprazole 5mg: Aripiprazole will be administered as an adjunctive treatment to escitalopram at an initial dose of 2.5 mg/day, titrated up to 5 mg/day based on tolerability. Treatment will last 8 weeks, after which aripiprazole will be tapered and discontinued. This intervention aims to evaluate the efficacy of dopaminergic augmentation in reducing pathological rumination symptoms.
Study summary
This randomized, single-blind (assessor-blind) controlled trial aims to investigate the efficacy of aripiprazole as an augmentation strategy for treating pathological rumination in patients with major depressive disorder (MDD). Pathological rumination-defined as repetitive, intrusive, and uncontrollable negative thinking-has been identified as a major transdiagnostic risk factor for the development, maintenance, and recurrence of depression. Even during clinical remission, ruminative symptoms often persist and strongly predict relapse.
Previous clinical observations and experimental studies suggest that aripiprazole, a partial dopamine D2 receptor agonist, can significantly improve cognitive symptoms and reduce rumination in MDD patients when added to selective serotonin reuptake inhibitors (SSRIs). However, rigorous randomized controlled trials (RCTs) directly targeting rumination and validating this effect remain limited.
In this study, patients with acute MDD episodes and high levels of rumination will be randomly assigned to receive either escitalopram monotherapy (20 mg/day) or escitalopram (20 mg/day) plus low-dose aripiprazole (2.5-5 mg/day) for 8 weeks. Clinical assessments will be repeated during the 8-week treatment phase, including interim monitoring visits for efficacy and safety. The primary clinical endpoint is the change in Ruminative Responses Scale (RRS) scores from baseline to week 8.The assignment will remain blinded to outcome assessors and data analysts, while patients and treating clinicians will remain unblinded due to dose titration and safety monitoring requirements.
Participants will undergo \[18F\]fallypride-PET-MRI scanning at baseline and and again at week 10, after tapering and discontinuation of aripiprazole during weeks 9-10, to measure striatal dopamine D2 receptor binding and explore its association with changes in rumination symptoms and treatment efficacy.
The primary outcome is the change in Ruminative Responses Scale (RRS) scores. Secondary outcomes include changes in depressive symptoms and dopamine D2 receptor availability. This trial will provide neurobiological insights into the dopaminergic mechanisms underlying pathological rumination and explore the therapeutic potential of D2 receptor modulation in this cognitive domain.
Eligibility
Inclusion Criteria:
For Patients With Major Depressive Disorder (MDD):
* Age 18 to 45 years
* Any sex
* Self-identified Han Chinese
* Right-handed
* Education level of junior high school or above
* Able to understand the informed consent form and complete self-report assessments
* Meets DSM-5 diagnostic criteria for Major Depressive Disorder (MDD) based on the Structured Clinical Interview for DSM-5 (SCID)
* Currently experiencing a major depressive episode
* 24-item Hamilton Depression Rating Scale (HAMD-24) score \>= 21 at screening/baseline
* Young Mania Rating Scale (YMRS) score \<= 5 at screening/baseline
* No psychotropic medication use, other than benzodiazepines, within 6 weeks before baseline
Pathological Rumination Group:
* Must meet all of the following criteria:
* Subjective experience of persistent and difficult-to-control ruminative thinking
* Interview-confirmed pathological rumination characterized by all of the following features:
* Repetitive
* Intrusive
* Difficult to disengage from
* Unproductive
* Occupying substantial mental resources
* Ruminative Responses Scale (RRS) score \>= 61
Low Rumination Group:
* Does not meet criteria for the Pathological Rumination Group
* Ruminative Responses Scale (RRS) score \< 61
For Healthy Controls:
* Age 18 to 45 years
* Any sex
* Self-identified Han Chinese
* Right-handed
* Education level of junior high school or above
* Able to understand the informed consent form and complete self-report assessments
* Does not meet DSM-5 diagnostic criteria for any current or past psychiatric disorder based on the Structured Clinical Interview for DSM-5 (SCID)
* 24-item Hamilton Depression Rating Scale (HAMD-24) score \< 8 at screening/baseline
* Young Mania Rating Scale (YMRS) score \<= 5 at screening/baseline
* No psychotropic medication use within 6 weeks before baseline
Exclusion Criteria:
For Patients With Major Depressive Disorder (MDD):
* Meets DSM-5 diagnostic criteria for any psychiatric disorder other than anxiety disorders
* Major depressive disorder with psychotic features
* Severe suicidal ideation or suicidal behavior
* History of traumatic brain injury or loss of consciousness
* Serious neurological or medical illness that, in the judgment of the investigators, may affect study participation or data interpretation, including but not limited to thyroid disorders, lupus, diabetes, active infection, or major trauma
* Cardiac pacemaker or any metallic implant incompatible with MRI or PET
* History of alcohol or substance dependence
* Pregnant or breastfeeding
* Personal history of epilepsy or family history of epilepsy in a first-degree relative
* Receipt of non-pharmacological psychiatric interventions within the past 6 months, including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or structured psychotherapy
For Healthy Controls:
* Meets DSM-5 diagnostic criteria for any current or past psychiatric disorder
* First-degree relative with a history of major psychiatric disorder
* Severe suicidal ideation or suicidal behavior
* History of traumatic brain injury or loss of consciousness
* Serious neurological or medical illness that, in the judgment of the investigators, may affect study participation or data interpretation, including but not limited to thyroid disorders, lupus, diabetes, active infection, or major trauma
* Cardiac pacemaker or any metallic implant incompatible with MRI or PET
* History of alcohol or substance dependence
* Pregnant or breastfeeding
* Personal history of epilepsy or family history of epilepsy in a first-degree relative
* Receipt of electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or structured psychotherapy within the past 6 months
Primary outcome measure(s)
- Change in Ruminative Responses Scale (RRS) score from baseline to week 8 — Baseline and week 8
The 22-item Ruminative Responses Scale (RRS) will be used to assess the severity of pathological rumination. The primary outcome is the change in total RRS score from baseline to the end of the 8-week treatment period. Total scores range from 22 to 88, with higher scores indicate more severe rumination.
Trial sites (1)
| Facility | City | Region | Status |
|---|
| The Second Xiangya Hospital of Central South University |
Changsha |
Hunan |
|
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