Neurobiological Mechanisms of Pathological Rumination and Effects of Aripiprazole

Investigation of the Neurobiological Mechanisms Underlying Pathological Rumination and the Pharmacological 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. 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Major Depressive Disorder (MDD); Rumination
• Intervention / Treatment: Drug: Escitalopram; Drug: Aripiprazole 5mg

Detailed Description

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. Clinical assessments will be performed repeatedly during the 8-week treatment phase, including interim monitoring visits for efficacy and safety, with the primary clinical endpoint assessed at week 8. 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 week 10, after tapering and discontinuation of aripiprazole during weeks 9-10). Additional clinical symptom scales will be obtained at week 10, concurrent with post-washout PET-MRI, to characterize symptom status and clinical change at the time of neuroimaging.

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 from baseline to week 8; 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.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410011
      • The Second Xiangya Hospital of Central South University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Escitalopram Only - MDD with Pathological Rumination; 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 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.
Experimental: Escitalopram + Aripiprazole - MDD with Pathological Rumination; 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; 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.
No Intervention: MDD with Low Rumination - Observational; MDD patients with low levels of rumination (RRS < 61) will receive no pharmacological intervention and serve as a naturalistic observation group.
No Intervention: Healthy Controls; Healthy individuals with no psychiatric history will serve as non-clinical imaging and behavioral controls.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 24-item Hamilton Depression Rating Scale (HAMD-24) score	Depression severity will be assessed using the 24-item HAMD. The outcome is the change in total score from baseline to week 8. This will help evaluate overall clinical improvement in depressive symptoms.	Baseline and week 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 10 in Striatal Dopamine D2/3 Receptor Binding Potential Measured by [18F]Fallypride PET	The outcome measure is the change from baseline to week 10 in prespecified striatal [18F]fallypride positron emission tomography (PET) binding potential relative to non-displaceable uptake (BPND), reflecting dopamine D2/3 receptor availability in prespecified striatal regions of interest. Follow-up PET imaging will be performed at week 10 after tapering and discontinuation of adjunctive aripiprazole during weeks 9 to 10.	Baseline and week 10
Change From Baseline to Week 10 in Prefrontal Cortex Dopamine D2/3 Receptor Binding Potential Measured by [18F]Fallypride PET	The outcome measure is the change from baseline to week 10 in [18F]fallypride positron emission tomography (PET) binding potential relative to non-displaceable uptake (BPND), reflecting dopamine D2/3 receptor availability in a prespecified prefrontal cortex region of interest. Follow-up PET imaging will be performed at week 10 after tapering and discontinuation of adjunctive aripiprazole during weeks 9 to 10.	Baseline and week 10
Change From Baseline to Week 10 in Prespecified Functional Connectivity Measured by Resting-State Functional Magnetic Resonance Imaging	The outcome measure is the change from baseline to week 10 in a prespecified resting-state functional magnetic resonance imaging (fMRI) functional connectivity metric derived from a predefined region of interest or network of interest. Follow-up MRI will be performed at week 10 concurrent with post-washout PET-MRI after tapering and discontinuation of adjunctive aripiprazole during weeks 9 to 10.	Baseline and week 10
Change From Baseline to Week 10 in Prespecified Neurite Density Index Measured by Diffusion MRI	The outcome measure is the change from baseline to week 10 in a prespecified neurite density index derived from diffusion magnetic resonance imaging using neurite orientation dispersion and density imaging (NODDI) in a predefined region of interest. Follow-up MRI will be performed at week 10 concurrent with post-washout PET-MRI after tapering and discontinuation of adjunctive aripiprazole during weeks 9 to 10.	Baseline to Week 10
Change From Baseline to Week 10 in Prespecified Neuromelanin-Sensitive Magnetic Resonance Imaging Signal in a Substantia Nigra Region of Interest	The outcome measure is the change from baseline to week 10 in a prespecified neuromelanin-sensitive magnetic resonance imaging (NM-MRI) signal metric derived from a predefined substantia nigra region of interest. The specific metric will be defined according to the prespecified imaging analysis plan. Follow-up MRI will be performed at week 10 concurrent with post-washout PET-MRI after tapering and discontinuation of adjunctive aripiprazole during weeks 9 to 10.	Baseline and week 10
Change From Baseline to Week 8 in Neurocognitive Composite Score	Neurocognition will be assessed using a standardized neurocognitive test battery. The outcome measure is the change in the prespecified neurocognitive composite score from baseline to week 8. Higher scores indicate better neurocognitive performance.	Baseline and week 8
Change From Baseline to Week 8 in Serum High-Sensitivity C-Reactive Protein Concentration	The outcome measure is the change in serum high-sensitivity C-reactive protein (hs-CRP) concentration from baseline to week 8 as an exploratory peripheral inflammatory biomarker.	Baseline and week 8
Change From Baseline to Week 8 in Serum Brain-Derived Neurotrophic Factor Concentration	The outcome measure is the change in serum brain-derived neurotrophic factor (BDNF) concentration from baseline to week 8 as an exploratory neurotrophic biomarker.	Baseline and week 8
Change From Baseline to Week 8 in Serum Cortisol Concentration	The outcome measure is the change in serum cortisol concentration from baseline to week 8 as an exploratory neuroendocrine biomarker.	Baseline and week 8
Change From Baseline to Week 8 in Prespecified Urinary Metabolomic Metric	The outcome measure is the change in a prespecified urinary metabolomic metric from baseline to week 8 as an exploratory biomarker of metabolic change. The specific metric will be defined according to the prespecified metabolomics analysis plan.	Baseline and week 8
Change From Baseline to Week 8 in Gut Microbiome Shannon Diversity Index	The outcome measure is the change in gut microbiome Shannon diversity index from baseline to week 8 as an exploratory stool-based microbiome biomarker.	Baseline and week 8
Change From Baseline to Week 8 in Montgomery-Åsberg Depression Rating Scale Total Score	The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated measure of depressive symptom severity. The outcome measure is the change in total MADRS score from baseline to week 8. Total scores range from 0 to 60, with higher scores indicating more severe depressive symptoms.	Baseline and week 8
Change From Baseline to Week 8 in Hamilton Anxiety Rating Scale Total Score	The Hamilton Anxiety Rating Scale (HAM-A) is a clinician-rated measure of anxiety symptom severity. The outcome measure is the change in total HAM-A score from baseline to week 8. Total scores range from 0 to 56, with higher scores indicating more severe anxiety symptoms.	Baseline and week 8
Change From Baseline to Week 8 in Perceived Deficits Questionnaire-Depression Total Score	The Perceived Deficits Questionnaire-Depression (PDQ-D) is a patient-reported measure of subjective cognitive dysfunction in depression. The outcome measure is the change in total PDQ-D score from baseline to week 8. Total scores range from 0 to 80, with higher scores indicating more severe subjective cognitive difficulties.	Baseline and week 8

Collaborators and Investigators

• Sponsor: Central South University
• Collaborators: National Natural Science Foundation of China; Second Xiangya Hospital of Central South University
• Investigators: Principal Investigator: Yan Zhang, Second Xiangya Hospital of Central South University

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2025
• Primary Completion (Actual): April 8, 2026
• Study Completion (Estimated): July 16, 2026

Study Registration Dates

• First Submitted: April 20, 2025
• First Submitted That Met QC Criteria: April 20, 2025
• First Posted (Actual): April 22, 2025

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Aripiprazole; Neuroimaging; Cognitive symptoms; PET-MRI; D2 receptor; Fallypride; Dopaminergic pathway
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Digestive System Diseases; Gastrointestinal Diseases; Mood Disorders; Feeding and Eating Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Rumination Syndrome; Depressive Disorder, Major; Neurobehavioral Manifestations; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Nitriles; Quinolones; Quinolines; Propylamines; Piperazines; Benzofurans; Aripiprazole; Escitalopram
• Other Study ID Numbers: LYG20230074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie the published results (including de-identified clinical and imaging data) will be available upon reasonable request from qualified researchers. Data will be shared after publication, with prior approval from the corresponding author and ethical oversight. Supporting documents such as the study protocol and statistical analysis plan will also be made available where applicable.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No