Neurobiological Mechanisms of Pathological Rumination and Effects of Aripiprazole

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. 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 post-treatment 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 old, any sex.

Han Chinese, right-handed.

Education level of junior high school or above, able to understand informed consent and complete self-report instruments.

Meets DSM-5 diagnostic criteria for Major Depressive Disorder (MDD) based on the SCID interview.

Currently experiencing a depressive episode:

HAMD-24 score ≥ 21

YMRS score ≤ 5

No psychotropic medication (except benzodiazepines) in the past 6 weeks.

Classified into one of two cognitive subgroups based on rumination:

Pathological Rumination Group: Must meet all three of the following:

1. Subjective experience (e.g., "I can't stop thinking about past regrets" or "I can't control painful thoughts...")
2. Interview-confirmed features of pathological rumination (all of the following):

   Repetitive Intrusive Difficult to disengage Unproductive Capturing mental capacity
3. Ruminative Responses Scale (RRS) score ≥ 61

Low Rumination Group: Does not meet the above criteria.

Exclusion Criteria:

* Meets DSM-5 criteria for psychiatric disorders other than anxiety disorders.

MDD with psychotic features.

Severe suicidal ideation or behavior.

History of traumatic brain injury or loss of consciousness.

Serious neurological or medical illness (e.g., thyroid disorders, lupus, diabetes, infection, trauma).

Cardiac pacemaker or any metallic implants incompatible with MRI/PET.

History of alcohol or substance dependence.

Pregnant or breastfeeding.

Personal or family history of epilepsy.

Underwent non-pharmacological psychiatric interventions (e.g., ECT, rTMS, psychotherapy) in the past 6 months.

Conditions3

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