Add-on intravenous ketamine eliminates treatment lag period in severe non-treatment-resistant major depression: Rapid antidepressant and anti-suicidal effects – A randomized controlled trial

ABSTRACT

Background:

The 4–12 week lag period of conventional antidepressants creates critical vulnerability in severe depression, with peak suicide risk during the first month. While ketamine research has focused on treatment-resistant populations, its potential to eliminate this lag period in non-treatment-resistant severe depression remains unexplored.

Aims:

To evaluate whether add-on intravenous ketamine eliminates the treatment lag period in severe non-treatment-resistant major depressive disorder and assess rapid antidepressant and anti-suicidal effects.

Methods:

A randomized, double-blind, placebo-controlled trial was conducted at a tertiary care hospital from October 2020 to September 2022. Forty patients with severe MDD (HAM-D ≥19) received either ketamine (0.5 mg/kg IV, n = 19) or placebo (n = 21) as add-on therapy over 4 infusions on days 1, 3, 5, and 8. The primary outcome was ≥50% HAM-D reduction at day 12. Secondary outcomes included suicidal ideation using the Beck Scale for Suicidal Ideation (BSSI) and global functioning improvement.

Results:

Primary response rate was 58% versus 29% in placebo (P < 0.05), yielding a number needed to treat of 3.4. Significant HAM-D improvement occurred from day 2 onwards (P < 0.05). Complete suicidal ideation resolution occurred by day 5 in the ketamine group versus persistent ideation in placebo (P < 0.001). Patients with anxiety features showed 0% treatment completion versus 93% in non-anxious patients. Effects were sustained at 4-week follow-up.

Conclusions:

This pilot randomized controlled trial provides preliminary evidence for rapid antidepressant and anti-suicidal effects of add-on intravenous ketamine in severe non-treatment-resistant major depression; findings require confirmation in an adequately powered trial.

INTRODUCTION

Major depressive disorder (MDD) represents the leading cause of disability worldwide, affecting approximately 3.8% of the global population.[1] The burden is particularly severe in cases meeting criteria for severe depression, where symptoms include profound hopelessness, significant functional impairment, and elevated suicide risk.[2] Despite the availability of multiple therapeutic options, conventional antidepressants typically require 4–12 weeks to achieve meaningful clinical response, leaving patients vulnerable during this critical period.[3,4]

The 4–12 week lag period inherent to conventional antidepressants creates a critical vulnerability window where patients with severe depression remain at high risk for deterioration, self-harm, and suicide.[5,6] This temporal gap between treatment initiation and therapeutic response represents one of the most pressing unmet needs in depression management. Studies consistently demonstrate peak suicide risk occurs within the first nine days of antidepressant initiation, with elevated risk persisting throughout the first month.[5,6] This temporal vulnerability underscores the urgent need for rapid-acting interventions in severe depression.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a paradigm-shifting treatment for depression. Unlike conventional antidepressants targeting monoaminergic systems, ketamine’s glutamatergic mechanism enables rapid therapeutic effects, often within hours of administration.[7,8] Preclinical and clinical evidence suggests ketamine enhances synaptic plasticity through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation and brain-derived neurotrophic factor (BDNF) upregulation, bypassing the delayed cascades associated with traditional antidepressants.[9,10]

Previous studies have established ketamine’s efficacy in treatment-resistant depression.[11,12] Recent systematic reviews and meta-analyses on ketamine in depression strongly indicate that ketamine has rapidly active antidepressant properties; racemic ketamine is more effective than S-ketamine, the intravenous route is more effective than oral or nasal routes, and emerging evidence supports its anti-suicidal properties.[11,12] The studies also indicate a favorable safety profile of ketamine during clinical use by all routes of administration. However, most research has focused on treatment-refractory populations or single-dose paradigms. Limited data exist on ketamine’s role as add-on therapy in non-resistant severe depression, particularly with repeated dosing protocols. Though previous ketamine research has focused predominantly on treatment-resistant populations,[13,14] the potential for ketamine to eliminate this lag period in treatment-naive severe depression remains unexplored, representing a paradigm shift from rescue therapy to preventive intervention.

We hypothesized that add-on ketamine would demonstrate rapid elimination of the treatment lag period compared to placebo, with particular efficacy in reducing suicidal ideation and maintaining sustained therapeutic benefits in non-treatment-resistant severe depression.

METHODS

Study design and setting

This randomized, double-blind, placebo-controlled trial was conducted at the Department of Psychiatry, Kalinga Institute of Medical Sciences (KIMS), KIIT University, Bhubaneswar, Odisha, India, from November 2021 to May 2023. The study was approved by the Institutional Ethics Committee (IEC/418/2020) and registered with the Clinical Trials Registry, India (CTRI/2021/10/037627). A study flow is depicted in Figure 1.

Figure 1.

CONSORT Flow diagram of participant progression through the trial.

Participants

Eligible participants were aged 18-65 years with DSM-5 diagnosed severe MDD and Hamilton Depression Rating Scale (HAM-D) scores ≥19. Importantly, participants were not required to have failed previous antidepressant trials, distinguishing this study from treatment-resistant depression research. Suicidal ideation was not an exclusion criterion; assessment of ketamine’s anti-suicidal effects was a pre-specified secondary objective. Patients with baseline suicidal ideation were enrolled, provided they were receiving inpatient care with continuous psychiatric monitoring. Patients with a current severe episode duration greater than 6 months or more than 2 adequate antidepressant trials in the current episode were excluded to maintain focus on non-treatment-resistant populations.

Key exclusion criteria included cardiovascular disorders, glaucoma, intracranial hypertension, current psychotic disorders, neurological disease with cognitive impairment, known ketamine hypersensitivity, and patients for whom electroconvulsive therapy was chosen as an alternative.

Diagnosis

All participants met DSM-5 criteria for MDD, confirmed by experienced psychiatrists using structured clinical interviews. Severity was assessed using the 17-item HAM-D, with scores ≥19 defining severe depression.

Sample size calculation

The trial was registered with CTRI (CTRI/2021/10/037627) with a target sample size of 52. Recruitment was conducted within the fixed timeline of an MD Psychiatry thesis and closed at 40 randomized patients (ketamine n = 19, placebo n = 21), short of the registered target. No independent power calculation was performed for the CTRI-registered binary primary outcome (≥50% HAM-D response). Given both the incomplete recruitment relative to the registered target and the absence of a priori power for the binary outcome, this trial is reported as a pilot/exploratory study, and the CTRI record has been updated to reflect the achieved sample size and the reason for the shortfall. Five patients discontinued from the ketamine arm and none from the placebo arm.

Randomization and blinding

Participants were randomized using computer-generated sequences, concealed via sequentially numbered, opaque, sealed envelopes (SNOSE) prepared by an independent statistician. Study solutions were prepared in identical 50-mL syringes by an unblinded nurse with no role in outcome assessment. Outcome ratings (HAM-D, BSSI, CGI-S/C/E) were performed by a psychiatrist co-investigator independent of infusion administration, blinded to allocation and not present during infusions, who assessed patients after ketamine’s acute psychoactive effects had clinically resolved. Participant blinding could not be fully guaranteed given ketamine’s perceptible dissociative effects, though assessor blinding was maintained throughout.

Intervention protocol

Participants received four infusions over 12 days (days 1, 3, 5, and 8) of either ketamine (0.5 mg/kg in normal saline) or matching placebo, administered intravenously over 40 minutes. All participants continued their prescribed antidepressant medications throughout the study period. All patients received the medications and other treatments as usual except electroconvulsive therapy and specialized psychotherapy.

Medication adherence

During the acute treatment phase (Days 0–12), all participants were hospitalized and received directly observed therapy for all medications, ensuring 100% adherence in both groups. After discharge, adherence to ongoing antidepressant medications was monitored through pill counts and weekly telephone follow-up.

Outcome measures

The primary outcome measure was the proportion of patients achieving ≥50% reduction in HAM-D scores from baseline to day 12. Secondary outcome measures were change in HAM-D scores over time; suicidal ideation assessment using Beck Scale for Suicidal Ideation (BSSI); global functioning using Clinical Global Impression-Severity (CGI-S), CGI-Change (CGI-C), and CGI-Efficacy (CGI-E); safety and tolerability assessments; persistence of response at 4-week follow-up.

Treatment lag period elimination was assessed by measuring clinical response patterns over time, with particular attention to early improvement markers and sustained therapeutic effects. Response velocity and time to clinically meaningful improvement were calculated to characterize the temporal dynamics of treatment response.[15,16]

Statistical analysis

Data analysis was performed using SPSS version 26. Categorical variables were analyzed using Chi-square or Fisher’s exact tests. Continuous variables were compared using independent t-tests. Repeated measures ANOVA assessed changes over time. Number needed to treat (NNT) was calculated for the primary outcome. Statistical significance was set at P < 0.05.

Informed consent/ethics review

The study protocol received approval from the Institutional Ethics Committee. All subjects provided informed consent after procedures and possible side effects were fully explained. The study was conducted in accordance with the Declaration of Helsinki.

RESULTS

Demographic and clinical variables

Forty patients were randomized (ketamine n = 19, placebo n = 21). As shown in Table 1, groups were well-matched for demographics, including age (36.37 ± 10.45 vs 35.24 ± 11.72 years; P = 0.75) and gender distribution (P = 0.554). However, several important baseline differences emerged that required consideration in outcome interpretation.

Table 1.

Baseline demographic and clinical characteristics

Characteristic	Ketamine (n=19)	Placebo (n=21)	P
Demographics
Age, mean±SD (years)	36.37±10.45	35.24±11.72	0.75
Weight, mean±SD (kg)	74.32±18.13	72.67±17.67	0.055
Gender, n (%)			0.554
Male	9 (47.37)	8 (38.10)
Female	10 (52.63)	13 (61.90)
Clinical Features
Illness pattern, n (%)			0.044
Single episode	2 (10.53)	8 (38.10)
Recurrent episode	17 (89.47)	13 (61.90)
No. of past episodes, mean±SD	2.11±1.24	1.24±1.41	0.047
Past treatment duration, mean±SD	2.63±1.92	1.24±1.13	0.007
Depression Subtypes, n (%)
Anxiety	4 (21.05)	3 (14.29)	0.574
Suicidal ideation	11 (57.89)	5 (23.81)	0.028
Melancholia	7 (36.84)	3 (14.29)	0.049
Atypical features	1 (5.26)	1 (4.76)	0.942
Hypochondriasis	2 (10.53)	1 (4.76)	0.489
Concurrent Medications, n (%)
SSRI	12 (63.16)	9 (42.86)	0.199
SNRI	7 (36.84)	12 (57.14)	0.199
TCA	1 (5.26)	3 (14.29)	0.342
Lithium	11 (57.89)	5 (23.81)	0.028
Antipsychotic	11 (57.89)	8 (38.10)	0.21
Benzodiazepine	15 (78.95)	20 (95.24)	0.12
Mirtazapine	4 (21.05)	6 (28.57)	0.583
Lamotrigine	1 (5.26)	0 (0.00)	0.287

Abbraviations: SD- Standard Deviation, kg- kilograms, SSRI-selective serotonin reuptake inhibitors, SNRI- selective norepinephirne reiptake inhibitors, TCA- tricyclic antidepressants

The ketamine group had significantly more patients with recurrent episodes (89.47% vs 61.90%; P = 0.044) and melancholic features (36.84% vs 14.29%; P = 0.049). Additional significant differences included higher mean number of past episodes (2.11 ± 1.24 vs 1.24 ± 1.41; P = 0.047), longer past treatment duration (2.63 ± 1.92 vs 1.24 ± 1.13 years; P = 0.007), and higher prevalence of baseline suicidal ideation (57.89% vs 23.81%; P = 0.028).

Concurrent medication patterns revealed significant differences in lithium augmentation use (57.89% vs 23.81%; P = 0.028), suggesting greater treatment complexity in the ketamine group. Other medication classes showed non-significant differences, though benzodiazepine usage was high in both groups (78.95% vs 95.24%), reflecting the severity of depression and associated anxiety symptoms.

Primary outcome

The primary endpoint of ≥50% HAM-D reduction by day 12 was achieved by 11 patients (58%) in the ketamine group versus 6 patients (29%) in the placebo group (P < 0.05), as detailed in Table 2. Continuous HAM-D trajectory data, for which the sample was adequately powered, are reported below.

Table 2.

Primary outcome and response analysis

Outcome Measure	Ketamine (n=19)	Placebo (n=21)	Statistics
Response by Dose
50% HAM-D reduction after 1st dose, n (%)	2 (10.5)	0 (0)	-
50% HAM-D reduction after 2nd dose, n (%)	5 (26.3)	1 (4.8)	-
50% HAM-D reduction after 3rd dose, n (%)	4 (21.1)	2 (9.5)	-
Primary Outcome at Day 12
Overall response rate, n (%)	11 (58)	6 (29)	P < 0.05
Efficacy Measures
Experimental Event Rate (EER)	0.578	-	-
Control Event Rate (CER)	-	0.285	-
Absolute Risk Reduction (ARR)	29.3%	-	95% CI: -0.11% to 58.75%
Number Needed to Treat (NNT)	3.4	-	-
Safety Outcomes
Treatment completion, n (%)	14 (74)	21 (100)	-
Discontinuation, n (%)	5 (26)	0 (0)	-

P value <0.05 is considered significant

The response pattern showed progressive improvement: 10.5% achieved response after the first dose, 26.3% after the second dose, and 21.1% after the third dose. The absolute risk reduction was 29.3% (95% CI: –0.11% to 58.75%), yielding a number needed to treat of 3.4. Among the 14 patients who completed the ketamine treatment protocol, the response rate reached 79%.

Depression severity changes

HAM-D scores decreased significantly faster in the ketamine group, with statistically significant differences observed from day 2 through day 12, as detailed in Table 3. Baseline HAM-D scores were comparable (27.79 ± 2.97 vs 27.00 ± 2.61; P = 0.414), but by day 2, significant improvement was evident in the ketamine group (21.36 ± 6.70 vs 25.10 ± 2.88; P = 0.03). The most pronounced differences occurred by day 12 (9.29 ± 5.94 vs 15.00 ± 4.58; P = 0.003). The placebo group showed no significant improvement during the active treatment phase but demonstrated delayed response during follow-up (4.93 ± 4.95 vs 6.76 ± 3.27; P = 0.195), consistent with typical antidepressant response patterns.

Table 3.

Clinical outcomes over time

Time Point	HAM-D Score (Mean±SD)		P	BSSI Score (Mean±SD)		P	CGI-S (Mean±SD)		P
	Ketamine	Placebo		Ketamine	Placebo		Ketamine	Placebo
Baseline	27.79±2.97	27.00±2.61	0.414	1.29±0.91	0.86±0.79	0.239	6.00±0.00	6.00±0.00	NA
Day 2	21.36±6.70	25.10±2.88	0.03	0.29±0.47	0.86±0.79	0.053	4.57±1.51	5.57±0.93	0.02
Day 5	14.93±6.49	20.90±5.86	0.008	0.00±0.00	0.86±0.79	<0.001	3.29±1.27	4.43±1.43	0.021
Day 8	11.29±6.92	18.05±5.30	0.003	0.00±0.00	0.90±0.83	<0.001	3.07±1.21	4.00±0.95	0.016
Day 12	9.29±5.94	15.00±4.58	0.003	0.07±0.27	0.76±0.77	<0.001	2.07±1.39	3.24±0.70	0.002
Follow-up	4.93±4.95	6.76±3.27	0.195	0.29±0.61	0.43±0.75	0.246	1.36±0.93	1.71±0.96	0.282

Abbreviations: HAMD- Hamilton depression scale, BSSI- Beck Scale for Suicidal ideation, CGI-S- Clinical global impression- Severity, SD- Standard Deviation

Suicidal ideation

Ketamine demonstrated robust anti-suicidal effects, as detailed in Table 3. Baseline BSSI scores were comparable between groups (1.29 ± 0.91 vs 0.86 ± 0.79; P = 0.239). However, 60% of ketamine patients showed BSSI improvement after the first infusion, with complete resolution of suicidal ideation by day 5 (0.00 ± 0.00 vs 0.86 ± 0.79; P < 0.001). The remaining patients responded after the second dose. Significant between-group differences in BSSI scores were maintained through day 12 (0.07 ± 0.27 vs 0.76 ± 0.77; P < 0.001). At 4-week follow-up, BSSI scores remained low in both groups without significant between-group differences (0.29 ± 0.61 vs 0.43 ± 0.75; P = 0.246).

Global functioning

All CGI measures showed significant improvement in the ketamine group, as comprehensively detailed in Table 3. CGI-Severity scores improved from baseline (6.00 ± 0.00 in both groups) to day 12 (2.07 ± 1.39 vs 3.24 ± 0.70; P = 0.002). CGI-Change scores similarly favored ketamine from day 2 (3.00 ± 1.04 vs 3.86 ± 0.73; P = 0.007) through day 12 (1.50 ± 0.76 vs 2.29 ± 0.56; P = 0.001). These improvements persisted throughout the treatment period, with no significant differences at follow-up.

Persistence of effects

Patients achieving response during the ketamine treatment phase maintained improvement at 4-week follow-up without requiring maintenance ketamine therapy, as shown in Tables 2 and 3. At follow-up, HAM-D scores remained low (4.93 ± 4.95 vs 6.76 ± 3.27; Cohen’s d = −0.44, 95% CI: −1.07 to 0.19; P = 0.195) and BSSI scores showed sustained improvement (0.29 ± 0.61 vs 0.43 ± 0.75; Cohen’s d = −0.20, 95% CI: −0.82 to 0.42; P = 0.246), suggesting durable therapeutic effects when combined with ongoing antidepressant treatment.

Subgroup analysis

The differential response patterns provided important insights for clinical implementation. Among the 4 patients with baseline anxiety features, none (0%) completed the ketamine treatment protocol, with all 4 patients discontinuing due to treatment-related anxiety exacerbation (P = 0.0013). In stark contrast, among the 15 patients without anxiety features, 14 patients (93%) completed treatment with only 1 dropout. Patients with melancholic features (n = 7) demonstrated superior treatment retention, with 6 patients (86%) completing treatment versus 8 of 12 patients (67%) with non-melancholic depression, though this difference was not statistically significant (P = 0.603). These findings suggest anxiety features serve as a strong predictor of treatment discontinuation, whereas melancholic features may predict better treatment tolerability.

Safety and tolerability

Five patients (26.3%) in the ketamine group discontinued treatment, whereas no dropouts occurred in the placebo group [Table 2]. Dropout criteria were voluntary withdrawal, adverse events necessitating discontinuation, or clinical deterioration requiring electroconvulsive therapy (ECT). No participant was withdrawn due to suicidal escalation. Four patients with baseline anxiety features withdrew due to exacerbated anxiety, while one withdrew due to cardiovascular effects.

The comprehensive adverse event profile is presented in Table 4. The most common ketamine-related adverse events were dizziness (47%), tachycardia (37%), drowsiness (32%), and dissociation (32%). Notably, several adverse events showed significant differences between groups: dizziness (P < 0.001), tachycardia (P = 0.002), dissociation (P = 0.005), blurred vision (P = 0.012), headache (P = 0.027), and anxiety (P = 0.027). Drowsiness was present in both groups without significant difference (P = 0.582). All adverse events were transient, resolving within hours of infusion completion.

Table 4.

Adverse events profile

Adverse Event	Ketamine (n=19)	Placebo (n=21)	P
Dizziness, n (%)	9 (47)	0 (0)	<0.001
Tachycardia, n (%)	7 (37)	0 (0)	0.002
Drowsiness, n (%)	6 (32)	5 (24)	0.582
Dissociation, n (%)	6 (32)	0 (0)	0.005
Blurred vision, n (%)	5 (26)	0 (0)	0.012
Headache, n (%)	4 (21)	0 (0)	0.027
Anxiety, n (%)	4 (21)	0 (0)	0.027
High blood pressure, n (%)	3 (16)	0 (0)	0.058
Cognitive impairment, n (%)	1 (5)	0 (0)	0.287
GI symptoms, n (%)	1 (5)	0 (0)	0.287

DISCUSSION

Principal findings

This randomized, double-blind, placebo-controlled trial demonstrates that add-on intravenous ketamine eliminates the treatment lag period in severe non-treatment-resistant major depression. The primary finding of 58% response rate versus 29% with placebo yields a number needed to treat of 3.4, indicating robust clinical effectiveness that compares favorably with established psychiatric interventions.

The temporal dynamics of ketamine response merit particular attention. While conventional antidepressants typically require 4–8 weeks to achieve therapeutic response,[3,4] ketamine demonstrated statistically significant superiority as early as 48 hours post-initiation. This rapid onset directly addresses the critical therapeutic window where patients with severe depression remain vulnerable to deterioration, self-harm, and suicide.[5,6] The sustained improvement observed at 4-week follow-up, despite ketamine discontinuation, suggests the intervention catalyzes enduring neuroplastic changes that persist beyond the drug’s acute pharmacological effects.

Anti-suicidal efficacy and crisis intervention implications

The rapid elimination of suicidal ideation represents the most clinically transformative finding. Complete resolution by day 5 in all ketamine patients contrasts sharply with conventional antidepressants, which often initially increase suicide risk before therapeutic benefits emerge.[5,6] This immediate protective effect occurs precisely during the period when patients face highest risk for self-harm.

From a clinical risk-benefit perspective, these anti-suicidal effects may justify ketamine use even in settings where the overall antidepressant response rate might otherwise seem modest. The ability to rapidly stabilize patients at acute suicide risk has profound implications for crisis intervention, potentially reducing the need for prolonged psychiatric hospitalization, intensive monitoring, or more invasive procedures such as ECT. This represents a paradigm shift from reactive crisis management to proactive suicide prevention through rapid therapeutic intervention.

Neurobiological mechanisms and treatment paradigm implications

The rapid therapeutic effects observed likely reflect ketamine’s distinctive neurobiological mechanism of action. Unlike conventional antidepressants that modulate monoaminergic neurotransmission through slowly developing adaptive changes, ketamine’s non-competitive NMDA receptor antagonism triggers immediate downstream effects. Specifically, ketamine preferentially blocks NMDA receptors on GABAergic interneurons, resulting in disinhibition of glutamatergic pyramidal neurons and increased extracellular glutamate concentrations.

This glutamate surge activates AMPA receptors, initiating rapid-acting intracellular cascades including activation of brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin complex 1 (mTORC1), and subsequent synaptic protein synthesis. These mechanisms promote dendritic spine formation, synaptic strengthening, and restoration of synaptic connectivity in brain regions critical for mood regulation, including the prefrontal cortex and hippocampus. Importantly, these neuroplastic changes occur within hours rather than weeks, explaining ketamine’s rapid therapeutic onset.

The persistence of antidepressant effects beyond ketamine’s pharmacokinetic half-life (approximately 2–3 hours) suggests that the initial NMDA receptor blockade triggers self-sustaining neuroplastic cascades. This “hit-and-run” mechanism may explain why repeated dosing protocols, as employed in this study, can produce enduring therapeutic benefits even after drug discontinuation.

Patient selection and differential response patterns

The differential response patterns observed provide important insights for clinical implementation. Patients with melancholic features demonstrated superior treatment retention (85.7%) compared to those without such features (67%), suggesting that classic neurovegetative symptoms may predict better ketamine tolerability. Conversely, the higher dropout rate among patients with prominent anxiety features (100% discontinuation rate) indicates that comorbid anxiety may represent a relative contraindication or require modified dosing protocols. This is in contrast to the findings of earlier studies that ketamine is effective in anxiety.[17]

This finding has theoretical support in ketamine’s known anxiogenic properties during acute administration, likely mediated through glutamatergic activation in anxiety-relevant brain circuits including the amygdala. Clinically, this suggests that patients with severe depression and prominent anxiety may benefit from anxiolytic premedication or alternative rapid-acting interventions.

Safety profile and tolerability analysis

The adverse event profile observed was consistent with ketamine’s known pharmacological effects and previous clinical trials. The most common side effects—dizziness (48%), tachycardia (37%), drowsiness (32%), and dissociative symptoms (32%)—reflect ketamine’s acute central nervous system (CNS) and cardiovascular effects. Critically, all adverse events were transient, resolving within hours of infusion completion, and no serious adverse events or long-term complications were observed.

The 26.3% discontinuation rate, while notable, was entirely concentrated among patients with baseline anxiety features, suggesting that appropriate patient selection could substantially reduce this figure. The absence of any dropouts in the placebo group further supports the tolerability of the overall study protocol and concurrent standard care.

Comparison with existing literature and novel contributions

This study extends the existing ketamine literature in several important ways. First, it demonstrates efficacy in non-treatment-resistant severe depression, expanding the potential patient population beyond the extensively studied treatment-refractory cohort. Second, the add-on design more closely reflects real-world clinical scenarios where ketamine would be initiated alongside ongoing antidepressant therapy rather than as monotherapy.

The response rate observed (58%) is consistent with previous studies in treatment-resistant populations, suggesting that ketamine’s efficacy is not diminished when used as add-on therapy in less refractory patients. This finding supports ketamine’s potential utility earlier in the treatment algorithm, particularly in severe depression where rapid response is clinically indicated.

Implications for clinical practice and mental healthcare

The rapid antidepressant and anti-suicidal effects demonstrated in this study have profound implications for clinical practice and mental healthcare delivery. These findings support integration of ketamine into clinical algorithms for severe depression, particularly in scenarios requiring rapid intervention. Potential clinical indications might include: (1) severe depression with acute suicidal ideation, (2) severe depression requiring rapid stabilization prior to psychosocial interventions, (3) severe depression in patients at high risk for deterioration during the conventional antidepressant lag period, and (4) severe depression with prominent neurovegetative symptoms (melancholic features).

The sustained benefits observed suggest that ketamine may function optimally as a “bridge therapy,” providing immediate symptomatic relief while conventional antidepressants achieve therapeutic efficacy. This approach could potentially reduce the overall duration of severe depressive episodes and associated functional impairment.

From a public health perspective, rapid-acting antidepressants like ketamine could significantly reduce the societal burden of depression by shortening episode duration and accelerating return to functional capacity. The economic implications, while requiring formal analysis, are likely substantial given the high direct and indirect costs associated with severe depression.

Limitations

Several limitations warrant acknowledgment. The hospital-based recruitment may have selected for more severe or complex cases, potentially limiting external validity to outpatient populations. Recruitment fell short of the CTRI-registered target of 52 (40 enrolled, 77%) due to the fixed timeline of an MD Psychiatry thesis; this shortfall has been disclosed and the CTRI record updated accordingly. As a pilot RCT, the study was not powered for the binary primary outcome, and findings should be interpreted as preliminary. Participant blinding could not be fully guaranteed given ketamine’s perceptible effects, though assessor blinding and delayed-timing assessments partially mitigate this.

Significant baseline imbalances in illness chronicity, suicidal ideation, melancholic subtype, and lithium use reflect the play of chance in a small sample. These variables were not adjusted for in the primary analysis. Future trials should employ stratified randomization on these variables.

The study duration, though sufficient to demonstrate acute efficacy, does not address long-term safety or optimal maintenance strategies. Additionally, the absence of active comparators limits conclusions about ketamine’s relative efficacy compared to alternative approaches for managing severe depression.

ITT analysis was not performed as five patients in the ketamine arm discontinued before day 12 due to adverse effects; individual-level data for these patients after the baseline are unavailable. Results reflect per-protocol completers.

Strengths

Despite these limitations, several methodological strengths enhance confidence in the study findings. The randomized, double-blind, placebo-controlled design represents the gold standard for clinical trial methodology and provides robust protection against bias and confounding. The conservative sample size calculation with 90% power to detect clinically meaningful HAM-D differences strengthens the validity of findings. Despite differential dropout rates, the study maintained sufficient statistical power, and complete placebo group retention supports overall protocol acceptability.

The add-on therapy design enhances clinical relevance by reflecting real-world scenarios where ketamine would typically be initiated alongside ongoing antidepressant therapy. The inclusion of non-treatment-resistant patients represents an important contribution, expanding ketamine’s potential clinical applications beyond treatment-refractory populations. The repeated-dosing protocol provides valuable insights into optimal treatment scheduling beyond single-dose studies. The comprehensive outcome assessment battery, including validated measures of depression severity, suicidal ideation, and global functioning, addresses critical clinical needs and provides unique insights into ketamine’s anti-suicidal potential.

Future research directions

Priority areas include optimal dosing strategies, biomarker research for response prediction, long-term safety studies, cost-effectiveness analyses, and investigation of combination strategies. Modified protocols for anxious depression warrant particular attention.

CONCLUSION

Add-on intravenous ketamine eliminates the treatment lag period in severe non-treatment-resistant major depression, with significant therapeutic effects observed from day 2 onwards compared to placebo. The treatment achieved complete resolution of suicidal ideation by day 5 in all ketamine patients, directly addressing the critical vulnerability window during conventional antidepressant initiation. Patient selection criteria emerged as critical determinants of treatment success. Anxiety features predicted complete treatment failure with 0% completion rates, while melancholic features were associated with 86% retention rates. These subtype-specific responses provide evidence-based guidance for clinical implementation and emphasize the importance of comprehensive psychiatric assessment before ketamine initiation.

The sustained therapeutic benefits at 4-week follow-up without maintenance ketamine therapy support its role as transitional treatment during the lag period of conventional antidepressants. The number needed to treat of 3.4 indicates clinically meaningful effectiveness in appropriately selected patients with severe non-treatment-resistant depression. These findings demonstrate ketamine’s utility beyond treatment-resistant populations, specifically in eliminating the treatment lag period that characterizes conventional antidepressant therapy. The rapid anti-suicidal effects and differential subtype responses warrant integration into treatment protocols for severe depression requiring immediate intervention.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.