Neurobiological Mechanisms of Pathological Rumination and Effects of Aripiprazole

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.

• 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.
• 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.

Primary outcomes

• Change in Ruminative Responses Scale (RRS) score from baseline to week 8 [Baseline and 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.

Secondary outcomes

• Change in 24-item Hamilton Depression Rating Scale (HAMD-24) score [Baseline and week 8]: 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.

Other outcomes

• Change From Baseline to Week 10 in Striatal Dopamine D2/3 Receptor Binding Potential Measured by [18F]Fallypride PET [Baseline and week 10]: 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.
• Change From Baseline to Week 10 in Prefrontal Cortex Dopamine D2/3 Receptor Binding Potential Measured by [18F]Fallypride PET [Baseline and week 10]: 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.
• Change From Baseline to Week 10 in Prespecified Functional Connectivity Measured by Resting-State Functional Magnetic Resonance Imaging [Baseline and week 10]: 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.
• Change From Baseline to Week 10 in Prespecified Neurite Density Index Measured by Diffusion MRI [Baseline to Week 10]: 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.
• Change From Baseline to Week 10 in Prespecified Neuromelanin-Sensitive Magnetic Resonance Imaging Signal in a Substantia Nigra Region of Interest [Baseline and week 10]: 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.
• Change From Baseline to Week 8 in Neurocognitive Composite Score [Baseline and week 8]: 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.
• Change From Baseline to Week 8 in Serum High-Sensitivity C-Reactive Protein Concentration [Baseline and week 8]: 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.
• Change From Baseline to Week 8 in Serum Brain-Derived Neurotrophic Factor Concentration [Baseline and week 8]: The outcome measure is the change in serum brain-derived neurotrophic factor (BDNF) concentration from baseline to week 8 as an exploratory neurotrophic biomarker.
• Change From Baseline to Week 8 in Serum Cortisol Concentration [Baseline and week 8]: The outcome measure is the change in serum cortisol concentration from baseline to week 8 as an exploratory neuroendocrine biomarker.
• Change From Baseline to Week 8 in Prespecified Urinary Metabolomic Metric [Baseline and week 8]: 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.
• Change From Baseline to Week 8 in Gut Microbiome Shannon Diversity Index [Baseline and week 8]: The outcome measure is the change in gut microbiome Shannon diversity index from baseline to week 8 as an exploratory stool-based microbiome biomarker.
• Change From Baseline to Week 8 in Montgomery-Åsberg Depression Rating Scale Total Score [Baseline and week 8]: 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.
• Change From Baseline to Week 8 in Hamilton Anxiety Rating Scale Total Score [Baseline and week 8]: 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.
• Change From Baseline to Week 8 in Perceived Deficits Questionnaire-Depression Total Score [Baseline and week 8]: 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.

Sex: All, ages: 18 Years to 45 Years, accepts healthy volunteers

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

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• Yan Zhang, Principal investigator, Second Xiangya Hospital of Central South University