Among adults with treatment-resistant depression in Sri Lanka, does adjunctive treatment with intravenous racemic ketamine followed by intranasal racemic ketamine produce significant improvement in depressive symptoms, suicidality, and functional impairment compared to baseline pre-treatment levels, while maintaining acceptable tolerability and safety?

Intervention (active): Racemic ketamine (ketamine).

This is an open-label, single-arm, uncontrolled pilot study. No control intervention (no placebo/active comparator/standard-therapy control) is planned.

Acute treatment phase (Weeks 1–4): Drug: Racemic ketamine (ketamine) Route: Intravenous infusion Dose: 0.5–1.0 mg/kg per session (flexible dose) Frequency: Twice weekly Duration: 4 weeks Notes: Treatment frequency may be reduced based on adverse effects/tolerability. Blood pressure monitoring is conducted before and during treatment sessions.

Maintenance treatment phase (Weeks 5–28; responders only): Eligibility for maintenance: Participants meeting response criteria after acute phase (?50% reduction in MADRS) Drug: Racemic ketamine (ketamine) Route: Intranasal administration Dose: 50–150 mg per session (flexible dose) Schedule: Weekly for the first 2 weeks, then every 2 weeks for the next 4 weeks, thereafter frequency adjusted based on clinical response Duration: 24 weeks

Non-responders: Participants who do not achieve response in the acute phase will discontinue ketamine treatment and will be managed as clinically appropriate.

Adults aged 18 to 64 years, inclusive.

Both males and females are eligible to participate.

Ability and willingness to provide written informed consent and comply with study procedures.

Meet DSM-5 diagnostic criteria for a depressive disorder (major depressive disorder or persistent depressive disorder), confirmed using the Mini International Neuropsychiatric Interview (MINI).

Presence of treatment-resistant depression, defined as non-response to at least two adequate trials of first-line antidepressant medications, with greater than 25% clinical improvement.

Moderate to severe depression, indicated by a Montgomery–Åsberg Depression Rating Scale (MADRS) score greater than 28 at screening.

Medically stable based on physical examination, vital signs, ECG, and laboratory investigations.

No other mental illness as the primary diagnosis, such as psychotic disorders, primary obsessive-compulsive disorder, or primary anxiety disorders.

Women of childbearing potential must use highly effective contraception throughout participation in the study.

Willing and able to comply with study procedures and treatment restrictions.

Previous non-response to treatment with ketamine or esketamine.

Presence of neurodegenerative disorders, significant cognitive impairment, or intellectual disability.

Clinically significant or uncontrolled hypertension.

Significant cardiovascular, gastrointestinal, pulmonary, neuroendocrine, or other medical conditions that may increase risk during ketamine treatment, as judged by the investigator.

Known allergy, hypersensitivity, or contraindication to ketamine or related compounds.

Current or past diagnosis of substance use disorder, or significant substance misuse including alcohol within the last two years.

Presence of significant Cluster B personality disorder or traits that may interfere with participation.

Pregnant or breastfeeding women, or those planning pregnancy during participation or within six weeks after the last ketamine dose.

Any psychosocial or clinical circumstance that, in the investigator’s judgment, makes participation not in the best interest of the participant.