Neurobiological Mechanisms of Pathological Rumination and Effects of Aripiprazole

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.

Revised Detailed Description（Single-Blind Assessor-Blind Version）

Background:

Pathological rumination is characterized by repetitive, intrusive, and difficult-to-control negative thinking that often persists even after depressive symptoms remit. It has been recognized as a proximal risk factor for the onset, maintenance, and recurrence of major depressive disorder (MDD). Recent meta-analyses and longitudinal studies have confirmed that rumination significantly contributes to poor treatment outcomes and is associated with trait-like persistence across diagnostic and symptomatic states.

Rationale:

Aripiprazole, a partial dopamine D2 receptor agonist, has shown potential in augmenting antidepressant therapy by improving cognitive control and reducing rumination. Clinical observations have suggested that adjunctive aripiprazole can significantly alleviate ruminative symptoms in MDD patients, yet high-quality randomized controlled trials (RCTs) directly targeting rumination as a primary outcome remain lacking. Dopaminergic dysfunction-particularly altered D2 receptor availability in the striatum-may underlie the neurobiological mechanisms of pathological rumination. Therefore, combining pharmacological intervention with molecular neuroimaging offers a promising translational approach to validate therapeutic targets.

Study Design:

This study adopts a randomized, single-blind (assessor-blind) controlled trial design. Eligible participants include unmedicated or drug-naive MDD patients with high levels of rumination and healthy controls. Patients with pathological rumination will be randomly assigned to one of two intervention arms:

Group I: Escitalopram (20 mg/day) + aripiprazole (2.5-5 mg/day) Group II: Escitalopram monotherapy (20 mg/day)

The aripiprazole dose will be titrated from 2.5 mg/day to a maximum of 5 mg/day based on tolerability. During weeks 9-10, aripiprazole will be tapered and discontinued, with escitalopram maintained. No additional psychotropic medications are allowed. Outcome assessors and data analysts will remain blinded to treatment allocation to minimize assessment bias.

Neuroimaging Assessment:

Participants will undergo two \[18F\]fallypride-PET-MRI scans (at baseline and at the end of treatment in week 8). The scanning protocol includes:

Intravenous injection of 5 mCi \[18F\]-fallypride Dynamic PET acquisition in three blocks (70 min, 50 min, 60 min) with resting intervals Image reconstruction of binding potential (BPND) maps using simplified reference tissue modeling (SRTM), with the cerebellum as the reference region

Outcome Measures:

Primary outcome: Change in Ruminative Responses Scale (RRS) score Secondary outcomes: Changes in depressive symptoms (e.g., HAMD), striatal D2 receptor BPND values, and the correlations between imaging changes and clinical improvement

Hypothesis:

Aberrant striatal dopamine D2 receptor availability is a neurobiological substrate of pathological rumination. Modulating D2 receptor activity via aripiprazole can reduce rumination and enhance treatment response. Neuroimaging markers are expected to correlate with symptom improvement, providing mechanistic insight into the dopaminergic contributions to depressive cognition.

Eligibility Criteria:
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.