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.

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