Comparison of Rapid Antidepressant and Antisuicidal Effects of Intramuscular Ketamine, Oral Ketamine, and Electroconvulsive Therapy in Patients With Major Depressive Disorder

Earlier clinical work had reported rapid antidepressant and antisuicidal effects of ketamine administered intravenously, and smaller case series and open trials suggested similar benefits with intramuscular (IM) and oral routes. Oral ketamine has lower bioavailability (about 20%–25%) than parenteral routes, so higher oral doses are often used; however, data directly comparing different routes of ketamine administration and their relative efficacy versus electroconvulsive therapy (ECT) are limited. Existing systematic reviews concluded that ketamine produces rapid symptom relief compared with placebo but left uncertainty about the durability of effects after one week and about non‑IV routes, while trials comparing repeated ketamine dosing with ECT remain sparse. Kheirabadi and colleagues designed a randomised pilot trial to compare repeated IM ketamine, repeated oral ketamine and routine ECT in patients with major depressive disorder (MDD) deemed suitable for ECT. The study aimed to compare antidepressant and antisuicidal effects, adverse events, haemodynamic safety and patient satisfaction across the three treatment modalities when given over a 3‑week course, with follow‑up to one month after treatment completion.

This was a randomised, parallel‑group pilot study approved by the institutional ethics committee and registered in the Iranian Registry of Clinical Trials. Forty‑five adult patients diagnosed with MDD who had suicidal ideation, treatment resistance, severe symptoms, or agitation and who had been referred for ECT were enrolled. The Methods section reports an age range of 20–70 years. Exclusion criteria included severe hepatic, cardiac, renal or urologic disease, prior psychotic, manic or hypomanic episodes, substance abuse, and depression due to a medical condition. Written informed consent was obtained from all participants. Participants were randomised by block allocation into three equal arms (n = 15 per arm). The interventions were: IM racemic ketamine 0.5 mg/kg administered into the gluteus medius, repeated for 6 to 9 injections over 3 weeks with 2–3 day intervals; oral R‑ketamine 1 mg/kg given every 2–3 days up to 6–9 administrations over 3 weeks (vials flavoured to mask bitter taste); and routine bifrontotemporal ECT delivered 6 to 9 sessions over 3 weeks under anaesthesia with succinylcholine, with stimulus titrated to achieve at least 20 seconds of tonic‑clonic seizure. Primary clinical outcomes were depressive symptoms measured with the 17‑item Hamilton Depression Rating Scale (HDRS‑17) and suicidal ideation measured with the Beck Scale for Suicidal Ideation (BSSI). Assessments occurred at baseline, 24 hours after the first intervention, weekly during the 3‑week intervention period, and at 1 and 4 weeks after the end of treatment. Vital signs (pulse rate, respiratory rate, systolic and diastolic blood pressure, SpO2) were monitored continuously during procedures and recorded 30 minutes post‑procedure. Adverse effects were documented. One month after the final session participants completed a four‑item Likert questionnaire assessing agreement to treatment, preference over prior medications, motivation to continue, and overall satisfaction. Statistical analysis used SPSS 20. Repeated measures analysis of variance (ANOVA) evaluated within‑ and between‑group changes over time; one‑way ANOVA with Tukey post hoc tests was used for quantitative comparisons where appropriate, and the Shapiro‑Wilk test was used to assess normality. Non‑parametric Kruskal‑Wallis tests compared the Likert satisfaction items because these did not follow a normal distribution.

Forty‑five patients (22 male, 23 female) aged between 20 and 70 years were randomised equally to the three treatment arms. The groups did not differ significantly in age or sex. A CONSORT flow diagram was referenced but not reproduced in the extracted text. Medication regimens that patients were taking prior to enrolment were generally continued unless contraindicated with the assigned treatment. All three interventions produced significant reductions in depressive symptoms over time: HDRS scores decreased significantly from baseline in each group (P < 0.001). Repeated measures ANOVA showed no significant main effect of intervention between groups, but the intervention-by-time interaction was significant, indicating differences in temporal patterns of response. For suicidal ideation, BSSI scores also fell significantly over time in all groups (P < 0.001). Although overall intervention and interaction P values for BSSI were reported as not significant, pointwise comparisons at 24 hours after the first intervention and at the second week showed significant differences between groups; post hoc analyses attributed these differences to contrasts between the ECT arm versus both the oral and IM ketamine arms. A Spearman correlation indicated a modest positive correlation between depression and suicide scores (r = 0.348, P = 0.03). Patient‑reported agreement, motivation, preference and overall satisfaction evaluated one month after treatment tended to be lower in the ECT group, but these differences did not reach statistical significance. Haemodynamic parameters (pulse rate, systolic and diastolic blood pressure, respiratory rate, SpO2) did not change significantly from baseline in any group. Adverse effects differed by modality. Most patients receiving IM or oral ketamine experienced transient dissociative symptoms and nystagmus lasting between 0.5 and 4 hours after dosing. In the ECT group cognitive and memory impairments were the predominant complications, reported to persist up to one month in 58.3% of ECT patients. Other reported ECT adverse events included headache, nausea and musculoskeletal pain in decreasing order. Tolerability was described as acceptable for both ECT and ketamine treatments in this sample.

Kheirabadi and colleagues interpret their findings to indicate that repeated administrations of IM ketamine (0.5 mg/kg) and oral ketamine (1 mg/kg) produced rapid antidepressant and antisuicidal effects that, during the 3‑week intervention period, were comparable to routine ECT. The authors note that the greatest reductions in HDRS and BSSI scores occurred at 24 hours after the first session in all three arms and remained below baseline at one‑month follow‑up. They report that the antidepressant effect was less durable on follow‑up than ECT, with ECT showing more favourable duration of antidepressant effect; by contrast, the antisuicidal effects of ketamine persisted and were similar to ECT up to one month after treatment. The authors highlight two time points during the intervention (24 hours and the second week) when suicide scores were significantly lower in both ketamine groups compared with ECT, suggesting a possible superiority of ketamine for rapid antisuicidal effects. Mechanistically, the discussion reiterates that ketamine’s rapid actions are thought to be mediated via NMDA receptor antagonism and downstream glutamatergic pathways that promote synaptogenesis, which contrasts with the slower onset of conventional monoaminergic antidepressants. The authors situate their results among prior reports that intravenous, oral and parenteral ketamine can yield rapid symptom relief and that repeated infusions may prolong benefit in some patients. They also cite heterogeneous findings from other trials, including some negative or inconclusive results in treatment‑resistant or chronically suicidal outpatient samples. Safety and tolerability are emphasised in the comparison of modalities. The investigators note that ketamine’s adverse effects in their sample (dissociation and nystagmus) were transient and manageable in a supervised setting, whereas ECT was associated with anaesthetic requirements and more persistent cognitive and memory complaints—memory impairment was present up to one month in over half of ECT recipients. Patient preference was lower for ECT, although overall satisfaction and motivation scores did not differ significantly across groups. The authors acknowledge several important limitations: small sample size and recruitment from a referral centre limiting generalisability; absence of plasma ketamine measurements so systemic exposure equivalence between routes cannot be confirmed; ethical constraints that prevented inclusion of a placebo arm; and impossibility of blinding to intervention. They also caution that ketamine may not be appropriate for patients with bipolar disorder, psychosis, substance dependence, or significant medical comorbidity, and they flag the risk of ketamine misuse. Finally, the discussion calls for larger trials with varied dosing regimens and longer follow‑up to better establish durability, optimal dosing and comparative efficacy versus ECT.

The study concludes that repeated doses of oral and IM ketamine probably have antidepressant and antisuicidal effects comparable with ECT in patients with severe or suicidal MDD, while producing fewer cognitive adverse effects and eliciting greater patient preference. The authors suggest that ketamine could be an acceptable alternative to ECT in this clinical context, but they emphasise the need for further research given the study’s limitations.