Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression

Suicide remains a major and rising public‑health problem, particularly among young people, and is closely associated with mood disorders such as major depressive disorder (MDD) and bipolar disorder. Existing anti‑suicidal interventions (for example lithium, clozapine, electroconvulsive therapy and psychotherapy) can be effective but typically take time to act or have important logistical and safety constraints. Earlier clinical and meta‑analytic research has identified rapid antidepressant and anti‑suicidal effects of ketamine and its S‑enantiomer esketamine, usually studied via intravenous or intranasal routes, but evidence specifically targeting suicidality as a primary outcome is limited and prior trials have often excluded patients at high suicide risk or used small samples. Surjan and colleagues aimed to examine whether repeated subcutaneous administrations of esketamine reduce suicidal ideation in treatment‑resistant major depressive episodes occurring in MDD or bipolar disorder. The study set out to evaluate efficacy using the item 10 score of the Montgomery‑Åsberg Depression Rating Scale (MADRS) as the primary endpoint, and to report safety and tolerability outcomes with a weekly six‑week dosing schedule delivered in a real‑world clinic setting. This investigation is presented as the first real‑world study to assess subcutaneous esketamine for suicidality in severely depressed patients.

The investigators conducted a retrospective, real‑world chart review at the Federal University of São Paulo. They examined 394 subcutaneous esketamine administrations recorded in clinical charts and reported results for suicidal ideation from 70 acutely depressed patients who met the study criteria. The protocol specified three primary endpoints overall (MADRS total score, anhedonia, and suicidal ideation), but the present report focuses on suicidality measured by MADRS item 10. Inclusion criteria required a DSM‑IV diagnosis of MDD or a bipolar major depressive episode confirmed with the Mini‑International Neuropsychiatric Interview, treatment resistance (failure to respond to two or more antidepressants or approved bipolar medications for at least 6 weeks), age 16–70 years, a baseline MADRS total score ≥25 and an item 10 score >2. Exclusion criteria included ketamine/esketamine hypersensitivity, lifetime ketamine/esketamine abuse or dependence, decompensated medical illness, acute psychosis, and recent severe cardiovascular events. Physical examinations, vitals and baseline blood tests were performed; participants continued their regular prescribed medications. Treatment consisted of once‑weekly subcutaneous injections of esketamine 50 mg/mL administered in the abdominal area by a certified psychiatrist with nurse assistance across six weeks. Doses started at 0.5 mg/kg and could be increased to 0.75 mg/kg and then 1.0 mg/kg according to clinical response, with injection volumes ranging from 0.45 mL to 2.2 mL. Response was defined as ≥50% reduction in MADRS total score. Blood pressure and heart rate were monitored every 15 minutes up to 120 minutes after each injection. MADRS ratings were collected by telephone at 24 hours post‑administration and in person at 7 days. All subjects who received at least one dose were included in an intention‑to‑treat analysis. The primary efficacy analysis used a mixed‑effects repeated‑measures model for change in item 10 MADRS scores from baseline to 24 hours post‑administration across administrations 1–6, with baseline MADRS total score as a covariate; fixed effects were time (treated categorically), diagnosis group (MDD versus bipolar depression) and their interaction, and a random subject effect accounted for intra‑subject correlations. Standard statistical tests (t‑tests, chi‑square/Fisher’s exact) described baseline characteristics; significance was set at p < 0.05.

Seventy acutely depressed patients were included: 39 with MDD and 31 with bipolar depression. Fifty‑nine patients (84%) completed the six‑administration protocol; all 70 patients received at least one injection and were analysed. Dose distribution was 5 patients (7%) at 0.5 mg/kg, 12 patients (17%) at 0.75 mg/kg, and 53 patients (76%) at 1.0 mg/kg. The bipolar group had greater treatment resistance by the Maudsley Staging Method (p = 0.011). A high proportion of patients (81.42%) had medical comorbidities including obesity (35.7%), hypertension (17.14%), diabetes (7.14%) and dyslipidaemia (11.4%). The extracted text does not provide precise numeric baseline item 10 MADRS or MADRS total scores by group in the results section. The mixed‑effects repeated‑measures analysis showed a significant main effect of time on item 10 MADRS scores (p < 0.0001), indicating change in suicidality over the treatment course, while the time × diagnosis interaction was not significant (p = 0.164). Post hoc testing found no significant differences between MDD and bipolar groups at any timepoint. Statistically significant reductions in suicidality were observed as early as 24 hours after the first subcutaneous esketamine administration (p < 0.001), with further decreases following repeated weekly administrations across the six‑week course. Regarding safety and tolerability, adverse events were described as mild and no participants withdrew for tolerability reasons. Mean heart rate remained similar to baseline during all administrations. A transient blood pressure increase—defined as systolic rise >30 mmHg and diastolic rise >15 mmHg—occurred in approximately 30% of patients; these increases were self‑limited and returned to baseline within 120 minutes. No differences in mean blood pressure or heart rate were observed across the three dose levels. The extracted text refers to further subgroup blood pressure analyses (for obesity and hypertension) but does not provide detailed numeric results in the sections supplied.

Surjan and colleagues interpret their real‑world findings as evidence that weekly subcutaneous esketamine is associated with rapid, sustained reductions in suicidal ideation among treatment‑resistant patients with MDD and bipolar depression. They note that significant anti‑suicidal effects appeared within 24 hours of the first injection and continued to improve with repeated administrations, with comparable efficacy between unipolar and bipolar groups. The authors situate these results within the broader ketamine/esketamine literature, which has shown rapid reductions in suicidal thoughts after single or repeated intravenous or intranasal administrations in several studies and meta‑analyses. They acknowledge that intranasal esketamine trials have yielded mixed findings for suicidality and that robust high‑quality evidence remains limited, especially for studies that enrol patients at higher suicide risk. The discussion outlines proposed neurobiological mechanisms for ketamine’s antisuicidal effects, including rapid restoration of connectivity in affective circuits, BDNF release and TrkB‑mTORC1 signalling, increased synaptogenesis, modulation of inflammation and the hypothalamic–pituitary–adrenal axis, and effects on multiple neurotransmitter systems; however, they emphasise that these mechanisms are not fully established and require more research. Key limitations acknowledged by the investigators include the retrospective, uncontrolled design, the relatively small sample size, and the absence of a dedicated suicidality instrument (relying instead on MADRS item 10). They further note that baseline suicidality severity assessed by MADRS item 10 was low in both groups and that pharmacokinetic data for the subcutaneous route remain limited; published estimates of bioavailability for subcutaneous and intramuscular administration vary and have been reported from small samples. Given these constraints, the authors recommend cautious interpretation and call for large, randomised, controlled and comparative studies to confirm efficacy, characterise optimal dosing and routes of administration, and better define safety in diverse patient populations.

The investigators conclude that weekly subcutaneous esketamine produced preliminary evidence of robust and sustained reductions in suicidal ideation in treatment‑resistant MDD and bipolar depression, with a favourable tolerability profile and transient cardiovascular effects. They propose the subcutaneous route as a potentially advantageous, simpler alternative to intravenous infusion, but state that definitive conclusions about comparative efficacy across administration routes cannot be drawn from the present data. The authors advocate for further controlled comparative trials to confirm these findings and to investigate route‑specific effects.