Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

Inclusion criteria

• Age: Adults aged 21 to 65 years.
• Diagnosis: Current Major Depressive Disorder (MDD) as confirmed by Structured Clinical Interview for DSM5 (SCID-5).
• Treatment Resistance: Failure to achieve remission with at least two antidepressants of adequate dose and duration (TRD criteria) as confirmed by SCID-5.
• Symptom Severity: Baseline Montgomery-Åsberg Depression Rating Scale (MADRS) ≥30.
• Suicidal Ideation: Participants with baseline passive or active suicidal ideation may be included, provided they do not meet criteria for inpatient admission and are deemed clinically stable for outpatient care. This will be measured with the Columbia Suicide Severity Rating Scale (C-SSRS).
• Consent: Ability to understand and voluntarily provide written informed consent.
• Contraception: For participants of reproductive potential, willingness to use at least one highly effective method of contraception (e.g., intrauterine device, hormonal contraception, sterilization) or two effective methods (e.g., barrier method plus spermicide) during the study and for at least one month after the final esketamine dose. Contraceptive method(s) will be documented at baseline via self-report on a standardized form and reaffirmed at each esketamine session by research staff. Participants who become pregnant or are unable to confirm adequate contraception will be withdrawn from the study for safety reasons.
• Availability: Willingness and ability to attend all scheduled sessions and complete study procedures.
• Motivation for Engagement: Demonstrates willingness and psychological readiness to engage in guided reflective work before and after esketamine dosing (as assessed during clinical intake).

Exclusion criteria

• Acute Suicide Risk: Immediate need for inpatient psychiatric hospitalization due to suicidal ideation with plan or intent as identified through the C-SSRS.
• Psychotic or Bipolar Disorders: Current diagnosis of bipolar I disorder (manic phase), schizophrenia, schizoaffective disorder, or other primary psychotic disorders if stated by participants as a past diagnosis or identified during the SCID-5.
• Substance Use Disorder: Active moderate to severe substance use disorder (except nicotine) in the past 6 months as self-identified by participant or during the SCID-5.
• Cognitive/Developmental Impairments: Intellectual disability, dementia, or other cognitive/developmental disorders that impair ability to engage meaningfully in structured psychotherapeutic sessions such as preparation or integration, per clinician judgment.
• Medical Contraindications: Any medical condition judged to pose undue risk during esketamine administration (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage, or hypersensitivity to esketamine/ketamine).
• Pregnancy/Breastfeeding: Current pregnancy or breastfeeding.
• Ongoing Structured Psychotherapy Likely to Confound Outcomes: Participation in any formal psychotherapy within the past 3 months that involves structured, weekly sessions focused on behavioral change or emotional processing (e.g., CBT, ACT, psychodynamic therapy), unless the therapy was completed or stabilized at a low-intensity level for at least 8 weeks prior to enrollment.
• Prior Non-Response to Esketamine: Six or more prior esketamine (≥56 mg) or IV ketamine sessions (0.4-0.7 mg/kg) without clinical response.
• Recent Ketamine Use: Use of ketamine/esketamine in the past 12 weeks.
• Inability to Consent: Any condition rendering the participant unable to provide informed consent.
• Prior Enrollment: Previous participation in this study.