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.

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.

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

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.

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.

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.

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).