This study will explore the effects of esketamine (Spravato®), an FDA-approved nasal spray, on adults diagnosed with treatment-resistant depression (TRD). All participants will receive esketamine as prescribed by a healthcare professional in a clinical setting.
The purpose of this research is to understand whether adding therapeutic support in the form of preparation and integration sessions - before and after the esketamine doses - can enhance the treatment experience and lead to longer-lasting improvements in mood and functioning.
Participants will be randomly assigned to one of two groups:
Esketamine with therapeutic support sessions (integration group) Esketamine without additional support (standard care group) Both groups will receive standard monitoring and psychiatric evaluation during the study. The support sessions offered in the integration group are designed to help participants prepare for their treatment sessions and make sense of their experiences afterward, using a structured, evidence-based approach.
The study will last approximately 8 weeks per participant, with follow-up assessments. The goal is to learn whether integration therapy can improve treatment outcomes, safety, and satisfaction for individuals with depression that hasn't responded to other treatments.
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.
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.
Parallel
Esketamine hydrochloride (intranasal)
DrugIntranasal esketamine (Spravato®), administered under medical supervision in accordance with FDA guidelines for treatment-resistant depression. Dosing schedule includes twice-weekly administration during weeks 1-4 (acute phase), followed by weekly or biweekly administration during weeks 5-8 (maintenance phase), based on clinical response and tolerability. All dosing occurs in a clinical setting with standard monitoring for at least two hours post-administration.
Integration Therapy
BehavioralBrief, structured psychotherapeutic sessions delivered before and after each esketamine dose, based on psychedelic-assisted therapy principles. Sessions are designed to support emotional safety, preparation for the treatment experience, and integration of psychological content that may arise. Conducted by trained clinicians following a standardized framework developed for this study. Only participants in the experimental arm receive this intervention.
Change From Baseline in Depression Severity as Assessed by MADRS
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to the end of acute treatment. The MADRS is a clinician-rated scale assessing depressive symptom severity, with scores ranging from 0 to 60. Higher scores indicate more severe depression; lower scores indicate symptom improvement.
Proportion of Participants Achieving Treatment Response (≥50% Reduction in MADRS)
Number of participants achieving treatment response, defined as a ≥50% reduction in MADRS total score from baseline. MADRS scores range from 0 to 60, with higher scores indicating greater depression severity.
Proportion of Participants Achieving Remission (MADRS <10)
Number of participants achieving remission, defined as a MADRS total score below 10 at the end of acute treatment. MADRS scores range from 0 to 60, with lower scores indicating fewer depressive symptoms.
Proportion of Participants Experiencing Depressive Relapse Confirmed by SCID-5
Number of participants meeting DSM-5 criteria for a new major depressive episode after achieving remission, as assessed using the Structured Clinical Interview for DSM-5 (SCID-5). This is a categorical diagnostic outcome (yes/no).
Change From Baseline in Functional Impairment as Assessed by WSAS
Change in Work and Social Adjustment Scale (WSAS) total score from baseline to the end of acute treatment. WSAS scores range from 0 to 40, with higher scores indicating greater functional impairment and lower scores indicating better functioning.
Subjective Experience Following Esketamine Administration (Qualitative Reflections)
Subjective experiences assessed through semi-structured interviews and written reflections exploring emotional, perceptual, and psychological experiences following esketamine sessions. Data will be analyzed using thematic qualitative analysis. This outcome does not use a numeric score.
Engagement With Psychedelic Integration as Assessed by Integration Scales
Engagement with preparation and integration processes assessed using Psychedelic Integration Scales. Scores reflect perceived meaning-making, insight, and behavioral integration. Scale scores range from lowest possible score (minimal engagement) to highest possible score (high engagement and integration); higher scores indicate greater integration.
Treatment Credibility and Expectancy as Assessed by the CEQ
Treatment credibility and expectancy assessed using the Credibility/Expectancy Questionnaire (CEQ). CEQ items are scored on Likert scales, with higher scores indicating greater perceived credibility and expectancy of benefit.
Therapeutic Alliance as Assessed by the Working Alliance Inventory-Short Form (WAI-SF)
Therapeutic alliance assessed using the Working Alliance Inventory-Short Form (WAI-SF), which measures agreement on goals, tasks, and therapeutic bond. Scores range from 12 to 84, with higher scores indicating stronger therapeutic alliance.
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