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. 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.

Conditions

• Major Depressive Disorder (MDD)
• Rumination

Interventions

DRUG

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.

DRUG

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.

Sponsors & Collaborators

• Second Xiangya Hospital of Central South University

  collaborator OTHER

• National Natural Science Foundation of China

  collaborator OTHER_GOV

• Central South University

  lead OTHER

Principal Investigators

• Yan Zhang · Second Xiangya Hospital of Central South University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2025-05-08

Primary Completion

2026-04-08

Completion

2026-05-01

Countries

• China

Study Locations