Neurobiological Mechanisms of Pathological Rumination and Effects of Aripiprazole

NCT06937476 | Active Not Recruiting

• 1 other identifier: LYG20230074
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Aripiprazole; Neuroimaging; Dopaminergic pathway; Fallypride; Randomized Controlled Trial; Cognitive symptoms; D2 receptor; PET-MRI

Outcome Measures

Primary Outcomes (1)

• Change in Ruminative Responses Scale (RRS) score from baseline to 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.

  Baseline and week 8

Secondary Outcomes (1)

• Change in 24-item Hamilton Depression Rating Scale (HAMD-24) score

  Baseline and week 8

Other Outcomes (14)

• Change From Baseline to Week 10 in Striatal Dopamine D2/3 Receptor Binding Potential Measured by [18F]Fallypride PET

  Baseline and week 10

• Change From Baseline to Week 10 in Prefrontal Cortex Dopamine D2/3 Receptor Binding Potential Measured by [18F]Fallypride PET

  Baseline and week 10

• Change From Baseline to Week 10 in Prespecified Functional Connectivity Measured by Resting-State Functional Magnetic Resonance Imaging

  Baseline and week 10

Study Arms (4)

Escitalopram Only - MDD with Pathological Rumination

EXPERIMENTAL

Patients diagnosed with major depressive disorder (MDD) and exhibiting pathological rumination will receive escitalopram monotherapy at 20 mg/day for 8 weeks.

Drug: Escitalopram

Escitalopram + Aripiprazole - MDD with Pathological Rumination

EXPERIMENTAL

Patients with MDD and pathological rumination will receive escitalopram (20 mg/day) and low-dose aripiprazole (2.5-5 mg/day) for 8 weeks, with titration based on tolerability.

Drug: Escitalopram; Drug: Aripiprazole 5mg

MDD with Low Rumination - Observational

NO INTERVENTION

MDD patients with low levels of rumination (RRS \< 61) will receive no pharmacological intervention and serve as a naturalistic observation group.

Healthy Controls

NO INTERVENTION

Healthy individuals with no psychiatric history will serve as non-clinical imaging and behavioral controls.

Interventions

Escitalopram DRUG

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.

Escitalopram + Aripiprazole - MDD with Pathological Rumination; Escitalopram Only - MDD with Pathological Rumination

Aripiprazole 5mg DRUG

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.

Escitalopram + Aripiprazole - MDD with Pathological Rumination

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Central South University: lead
• Second Xiangya Hospital of Central South University: collaborator
• National Natural Science Foundation of China: collaborator

Study Sites (1)

The Second Xiangya Hospital of Central South University

Changsha, Hunan, 410011, China

Location

Related Publications (4)

• van der Velden AM, Scholl J, Elmholdt EM, Fjorback LO, Harmer CJ, Lazar SW, O'Toole MS, Smallwood J, Roepstorff A, Kuyken W. Mindfulness Training Changes Brain Dynamics During Depressive Rumination: A Randomized Controlled Trial. Biol Psychiatry. 2023 Feb 1;93(3):233-242. doi: 10.1016/j.biopsych.2022.06.038. Epub 2022 Jul 22.

  PMID: 36328822 BACKGROUND

• Song AK, Hay KR, Trujillo P, Aumann M, Stark AJ, Yan Y, Kang H, Donahue MJ, Zald DH, Claassen DO. Amphetamine-induced dopamine release and impulsivity in Parkinson's disease. Brain. 2022 Oct 21;145(10):3488-3499. doi: 10.1093/brain/awab487.

  PMID: 34951464 BACKGROUND

• Wang Y, Lu Z, Xun G. Effect of aripiprazole on promoting cognitive function and enhancing clinical efficacy in patients with first-episode depression on escitalopram: A randomized controlled trial. J Affect Disord. 2024 Jan 1;344:159-168. doi: 10.1016/j.jad.2023.10.038. Epub 2023 Oct 10.

  PMID: 37827257 BACKGROUND

• Ehring T. Thinking too much: rumination and psychopathology. World Psychiatry. 2021 Oct;20(3):441-442. doi: 10.1002/wps.20910. No abstract available.

  PMID: 34505392 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Rumination Syndrome; Neurobehavioral Manifestations

Interventions

Escitalopram; Aripiprazole

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Gastrointestinal Diseases; Digestive System Diseases; Feeding and Eating Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Quinolones; Quinolines

Study Officials

• Yan Zhang

  Second Xiangya Hospital of Central South University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Only the outcome assessors and data analysts will be blinded to treatment allocation. Study participants and clinical investigators will remain unblinded due to the need for dosage adjustment and monitoring. Rater blinding is maintained to reduce assessment bias in outcome measures such as the Ruminative Responses Scale (RRS) and Hamilton Depression Rating Scale (HAMD).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Department of Psychiatry, The Second Xiangya Hospital

Model Details: This study involves four parallel groups: (1) pathological-rumination MDD patients treated with escitalopram alone (n=24), (2) pathological-rumination MDD patients treated with escitalopram plus aripiprazole (n=24), (3) non-pathological-rumination MDD patients without intervention (n=24), and (4) healthy controls without intervention (n=36). The increased sample size of the healthy control group is intended to provide a representative normative reference for clinical and imaging measures.

Study Record Dates

• First Submitted: April 20, 2025
• First Posted: April 22, 2025
• Study Start: May 8, 2025
• Primary Completion: April 8, 2026
• Study Completion: May 1, 2026
• Last Updated: April 16, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Individual participant data (IPD) and supporting documents will be available beginning 6 months after publication of the main results and will remain available for up to 5 years, or as long as the dataset is maintained by the research team.
• Access Criteria: De-identified clinical and imaging data will be made available to qualified researchers with a methodologically sound proposal, subject to approval by the principal investigator and institutional ethics board. Data requests can be submitted by email and will require signing a data use agreement.

Locations

CN (1)