ESKPSY: Esketamine in Real-World Settings: Clinical Outcomes, Predictors of Response, Life Functioning and Biological Pathways
Conditions: Depression and Quality of Life, Treatment Resistant Depression (TRD), Anhedonia, Apathy, Anxiety, Cognition, Temperament, Psychiatric Comorbidities
Sponsor: Riccardo Guglielmo

Study Protocol 
Official Title 
ESKPSY: Esketamine in Real-World Settings – Clinical Outcomes, Predictors of Response, Life 
Functioning and Biological Pathways 
NCT Number 
To be assigned by ClinicalTrials.gov 
Date 
August 2025 
 
1. Background and Rationale 
Treatment-resistant depression (TRD) represents a significant clinical challenge, with limited 
effective pharmacological options. Esketamine, a non-competitive NMDA receptor antagonist, has 
shown promise in improving symptoms in TRD patients, with a rapid onset of antidepressant 
action. However, not all patients respond equally, and predictors of treatment response remain 
unclear. 
Emerging literature suggests that clinical, biological (including genetic polymorphisms and 
neuroimaging), and psychosocial variables may contribute to esketamine response variability. 
Building on studies such as Guglielmo et al. (2023), which explored the role of temperament and 
cumulative resistance, this study aims to deepen understanding of real-world predictors of 
esketamine effectiveness and safety. 
 
2. Study Objectives 
Primary Objective: 
• 
To identify predictive factors (clinical, biological, psychophysical, and functional) of 
clinical response to esketamine in patients with treatment-resistant depression. 
Secondary Objectives: 
• 
To evaluate the effectiveness and safety of esketamine in a real-world clinical setting. 
• 
To explore changes in psychosocial and occupational functioning over time. 
• 
To investigate biological pathways associated with treatment response, including genetic 
polymorphisms (SNPs), neuroimaging data, and psychophysical tasks (e.g., temporal 
bisection). 
 
3. Study Design 
• 
Study Type: Observational 

• 
Design: Prospective, longitudinal, single-arm (case-only) 
• 
Duration: From enrollment to 12 months of treatment 
• 
Setting: Real-world clinical practice across outpatient psychiatric centers in Italy 
• 
Estimated Enrollment: 100 
 
4. Population 
Inclusion Criteria: 
• 
Adults (≥18 years) diagnosed with Major Depressive Disorder (MDD), meeting criteria for 
treatment-resistant depression (failure of ≥2 antidepressants) 
• 
Eligible for esketamine treatment as per national guidelines 
• 
Ability to provide informed consent 
Exclusion Criteria: 
• 
Current diagnosis of psychotic disorder 
• 
Contraindications to esketamine 
• 
Substance use disorder (moderate to severe) in the past 6 months 
• 
Significant cognitive impairment or neurological conditions 
 
5. Intervention (Observed Treatment) 
• 
Esketamine nasal spray, administered in accordance with the approved product label: 
o Dosage ranging from 28 mg to 84 mg per week 
o Twice-weekly administration during the first month, followed by weekly 
maintenance 
 
6. Outcome Measures 
Primary Outcome: 
• 
Identification of predictive factors of clinical response to esketamine, measured using 
standard clinical scales (e.g., MADRS) at baseline and regular follow-ups. 
Secondary Outcomes: 
• 
Changes in depressive symptoms over time 
• 
Changes in social and occupational functioning  
• 
Safety and tolerability (adverse events monitoring) 
• 
Associations between response and: 
o Genetic polymorphisms (SNPs) 
o Neuroimaging features (e.g., structural and functional MRI) 
o Psychophysical performance (e.g., temporal bisection tasks) 

 
7. Data Collection and Timepoints 
• 
Baseline: Clinical, demographic, neuroimaging, genetic, psychophysical assessments 
• 
Follow-ups: At 1, 3, 6 and 12 months 
o Clinical scales 
o Functional assessments 
o Safety monitoring 
 
8. Statistical Analysis Plan (SAP) 
• 
Descriptive statistics for demographic and clinical variables 
• 
Logistic regression and machine learning models to identify predictive factors of response 
• 
Longitudinal analysis (mixed-effects models) for symptom trajectories and functioning 
• 
Correction for multiple comparisons where appropriate (e.g., false discovery rate) 
 
9. Ethics and Dissemination 
• 
The study will be conducted in accordance with the Declaration of Helsinki. 
• 
Ethical approval has been or will be obtained from local institutional review boards. 
• 
Results will be submitted for publication in peer-reviewed journals and presented at 
international psychiatric conferences. 
 
10. Funding and Conflicts of Interest 
• 
The investigators declare no conflicts of interest unless otherwise stated.