Major depressive disorder (MDD) is a major cause of disability and is associated with prolonged emotional distress, impaired social and occupational functioning, and excess healthcare utilization. Despite multiple pharmacological options, some patients fail to achieve satisfactory improvement. Treatment-resistant depression (TRD) is commonly characterized by nonresponse to at least two adequate antidepressant trials during the same depressive episode [1]. Conventional antidepressants primarily influence monoaminergic signaling and often require weeks to achieve maximal benefit. Increasing attention has therefore focused on glutamatergic signaling and synaptic plasticity. Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects in several clinical investigations [2,3]. Racemic ketamine contains R- and S-enantiomers. Esketamine, the S-enantiomer, has been developed as an intranasal treatment with supervised administration. Evidence from randomized trials supports antidepressant benefit in selected TRD populations [4,5]. However, intranasal esketamine and intravenous racemic ketamine differ in dosing, exposure, monitoring and accessibility. Direct comparisons remain important for evaluating therapeutic outcomes and acute adverse events. An intravenous head-to-head trial reported noninferiority of esketamine to racemic ketamine for short-term outcomes, although its findings should not be assumed to apply directly to intranasal versus intravenous treatment [6]. This comparative report addresses depressive symptom improvement, clinical response, remission and tolerability in an institutional TRD cohort. Aim and Objectives To compare changes in MADRS scores between esketamine and ketamine; determine treatment response (≥50% MADRS reduction) and remission (MADRS ≤10); describe temporal improvement; and assess adverse reactions, treatment completion and discontinuation.

Study design, setting and duration A hospital-based comparative clinical study was conducted through the Department of Pharmacology, Maheshwara Medical College, Isnapur, Sangareddy, Telangana, in coordination with Psychiatry. The study period extended from November 2025 to April 2026 (six months). Study population The study included 80 adult patients with treatment-resistant MDD, divided into two equal groups: esketamine (n=40) and racemic ketamine (n=40). Adults aged 18–65 years with inadequate response to at least two adequate antidepressant courses met the inclusion criteria. Eligibility criteria Exclusion criteria included primary psychotic or bipolar disorders, clinically unstable cardiovascular conditions, severe uncontrolled medical or neurological illness, active substance dependence, known hypersensitivity, pregnancy or breastfeeding, and contraindications to ketamine-derived therapies. Treatment protocols The esketamine group received intranasal esketamine 56–84 mg under supervision twice weekly during a four-week induction period. The ketamine group received intravenous racemic ketamine 0.5 mg/kg infused over 40 minutes twice weekly for four weeks. Background antidepressant treatment was continued as clinically indicated. Outcomes and follow-up MADRS (range 0–60) was evaluated at baseline and Days 1, 7, 14 and 28. The primary endpoint was change from baseline to Day 28. Response was defined as ≥50% reduction and remission as MADRS ≤10. Safety assessment covered dissociation, dizziness, nausea, sedation, headache, perceptual changes, vomiting, transient blood-pressure elevations and serious events. Statistical analysis Continuous variables were expressed as mean ± standard deviation and categorical variables as number (percentage). Independent-samples t-tests were used for continuous between-group comparisons, while Fisher’s exact tests were used for categorical outcomes. A two-sided p-value of less than 0.05 was considered statistically significant.

The study included 80 patients, with 40 in each treatment group. Baseline demographic and clinical characteristics were comparable between groups (Table 1). Table 1. Baseline demographic and clinical characteristics Parameter Esketamine (n=40) Ketamine (n=40) p-value Age (years) 39.8 ± 10.2 41.1 ± 9.8 0.563 Male 18 (45.0%) 19 (47.5%) 1.000 Female 22 (55.0%) 21 (52.5%) 1.000 Depression duration (years) 6.1 ± 2.9 6.4 ± 3.1 0.656 Previous antidepressant trials 3.2 ± 1.1 3.1 ± 1.2 0.699 Baseline MADRS 34.6 ± 5.2 34.1 ± 5.5 0.677 Family history of depression 12 (30.0%) 15 (37.5%) 0.637 Associated anxiety symptoms 22 (55.0%) 21 (52.5%) 1.000 Depressive symptom severity Mean MADRS scores decreased in both groups. At Day 28, scores were 13.0 ± 7.0 in the esketamine group and 16.4 ± 7.4 in the ketamine group (p=0.038); corresponding mean reductions were 21.6 ± 7.4 and 17.7 ± 7.8 (p=0.024) (Table 2; Figure 1). Table 2. MADRS scores across assessment visits Time point Esketamine (n=40) Ketamine (n=40) p-value Baseline 34.6 ± 5.2 34.1 ± 5.5 0.677 Day 1 27.4 ± 6.2 25.5 ± 6.5 0.185 Day 7 21.0 ± 6.6 21.7 ± 6.7 0.639 Day 14 16.7 ± 6.9 18.8 ± 7.1 0.184 Day 28 13.0 ± 7.0 16.4 ± 7.4 0.038 Change, baseline to Day 28 21.6 ± 7.4 17.7 ± 7.8 0.024 Figure 1. Trends in mean MADRS scores during four weeks of treatment. Response and remission At Day 28, clinical response was 75.0% versus 62.5% and remission was 50.0% versus 35.0% for esketamine and ketamine, respectively. These categorical comparisons did not reach statistical significance (Table 3; Figure 2). Table 3. Treatment response and remission Outcome Esketamine (n=40) Ketamine (n=40) p-value Day 7 response 9 (22.5%) 11 (27.5%) 0.797 Day 14 response 22 (55.0%) 21 (52.5%) 1.000 Day 28 response 30 (75.0%) 25 (62.5%) 0.335 Day 28 remission 20 (50.0%) 14 (35.0%) 0.258 Day 28 nonresponse 10 (25.0%) 15 (37.5%) 0.335 Safety and treatment completion Dissociation, dizziness, nausea and transient blood-pressure elevation were among the most frequently reported treatment-emergent adverse events (Table 4). Completion of planned induction therapy was 90.0% and 85.0% in the esketamine and ketamine groups, respectively (Table 5). Table 4. Treatment-emergent adverse events Adverse event Esketamine (n=40) Ketamine (n=40) p-value Dissociation 12 (30.0%) 15 (37.5%) 0.637 Dizziness 10 (25.0%) 14 (35.0%) 0.465 Nausea 9 (22.5%) 11 (27.5%) 0.797 Sedation 8 (20.0%) 12 (30.0%) 0.439 Headache 7 (17.5%) 10 (25.0%) 0.586 Transient hypertension 6 (15.0%) 10 (25.0%) 0.402 Perceptual disturbance 4 (10.0%) 6 (15.0%) 0.737 Vomiting 3 (7.5%) 5 (12.5%) 0.712 Serious adverse event 0 (0.0%) 0 (0.0%) — Table 5. Treatment completion and tolerability Parameter Esketamine (n=40) Ketamine (n=40) Completed induction 36 (90.0%) 34 (85.0%) Any discontinuation 4 (10.0%) 6 (15.0%) Discontinuation due to adverse events 2 (5.0%) 3 (7.5%) Other discontinuations 2 (5.0%) 3 (7.5%) Completed eight sessions 36 (90.0%) 34 (85.0%)

Ketamine-based pharmacotherapy has expanded treatment options for TRD by targeting glutamatergic neurotransmission rather than the monoaminergic mechanisms of conventional antidepressants. In this comparison, both treatment groups showed improvements in depressive symptom severity, with a greater mean reduction in Day-28 MADRS scores in the esketamine group. Popova et al. reported antidepressant benefit with intranasal esketamine combined with a newly initiated oral antidepressant [5]. Correia-Melo et al. directly compared intravenous esketamine and racemic ketamine and reported short-term noninferiority of esketamine, although that intravenous design differs from a route-mixed comparison [6]. Murrough et al. also demonstrated rapid efficacy of intravenous ketamine in TRD [8]. The early symptom changes with ketamine and subsequent improvement in both groups emphasize the importance of assessment timing. Rapid initial improvement should be distinguished from remission and the durability of benefit. At Day 28, response and remission rates were numerically higher with esketamine, although categorical between-group differences were not statistically significant. Daly et al. evaluated relapse prevention with esketamine in responders/remitters [9], highlighting the importance of continuing follow-up after acute treatment. An induction-period analysis alone cannot determine sustained remission, relapse risk or long-term functional outcomes. Dissociation, dizziness, sedation, nausea and transient blood-pressure elevation are recognized effects of ketamine-derived therapies. The SUSTAIN-2 long-term safety study described clinically relevant events associated with esketamine, supporting supervised administration and monitoring [10]. Acute adverse-event percentages in a small cohort should not be interpreted as definitive estimates of comparative safety. The study had several limitations, including its sample size of 80 patients, short duration of outcome assessment, differences in treatment administration routes and possible effects of concomitant therapy. Differences in baseline clinical characteristics and treatment allocation may also influence comparative outcomes. Longer follow-up and larger controlled studies would strengthen the evidence concerning sustained efficacy and uncommon adverse events.

Esketamine and racemic ketamine were associated with improvements in depressive symptom severity over four weeks of treatment. The esketamine group showed a greater mean reduction in MADRS scores at Day 28, whereas differences in clinical response and remission rates were not statistically significant. Both treatments had adverse events requiring careful patient selection and clinical monitoring.

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