In this randomized double‑blind trial of 84 outpatients with treatment‑resistant depression and prominent suicidal ideation, a single low‑dose ketamine infusion (35mg/70kg) produced greater antidepressant effects than midazolam lasting up to 14 days and antisuicidal effects lasting about 5 days. Benefits were most evident in patients whose current episode was under 24 months or who had failed ≤4 antidepressants, and the infusion was safe and well tolerated.
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Background
The benefits of low-dose ketamine for patients with treatment-resistant depression (TRD) and prominent suicidal ideation require further investigation. The effects of treatment refractoriness, the duration of the current depressive episode, and the number of prior antidepressant failures on ketamine efficacy also require clarification.
Methods
We recruited 84 outpatients with TRD and prominent suicidal ideation—defined as a score ≥4 on item 10 of the Montgomery–Åsberg Depression Rating Scale (MADRS)—and randomized them into 2 groups to receive 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. We assessed depressive and suicidal symptoms prior to infusion; 240 minutes post infusion; and 2, 3, 5, 7, and 14 days post infusion.
Results
According to the MADRS scores, the antidepressant effect (P = .035) was significantly noted in the ketamine group up to 14 days than in the midazolam group. However, the antisuicidal effect of ketamine, as measured by the Columbia-Suicide Severity Rating Scale Ideation Severity Subscale (P = .040) and MADRS item 10 (P = .023), persisted only 5 days post infusion. Furthermore, the antidepressant and antisuicidal effects of ketamine infusion were noted particularly in patients whose current depressive episode lasted <24 months or whose number of failed antidepressants was ≤4.
Conclusions
Low-dose ketamine infusion is a safe, tolerable, and effective treatment for patients with TRD and prominent suicidal ideation. Our study highlights the importance of timing; specifically, ketamine is more likely to achieve therapeutic response when the current depressive episode lasted <24 months and the number of failed antidepressants is ≤4.
Su and colleagues situate their study in the context of rising global suicide rates and a growing literature on rapid antisuicidal effects of low-dose ketamine. They note prior randomised trials and meta-analyses showing rapid reductions in suicidal ideation, but also highlight heterogeneity in those samples and in treatment refractoriness; some prior trials included many participants who were not in major depressive episodes or had low levels of treatment resistance, which may have influenced durability of response. The authors further point to inconsistent findings about how long ketamine's antisuicidal effect endures in people with treatment-resistant depression (TRD). This study therefore set out to test whether a single low-dose ketamine infusion (0.5 mg/kg) produces rapid and sustained antidepressant and antisuicidal effects in outpatients with TRD and prominent suicidal ideation, compared with an active control (0.045 mg/kg midazolam). Su and colleagues also aimed to examine whether clinical features of refractoriness — level of treatment resistance, duration of the current depressive episode, and number of prior antidepressant failures — moderated ketamine's effects. The hypothesis was that ketamine would show rapid benefits that would be greater and more durable among patients without severe refractoriness or chronic episodes.
This was a randomised, double-blind, midazolam-controlled trial conducted in adult outpatients aged 20–64 years diagnosed with major depressive disorder (DSM-5) who had not responded adequately to at least two antidepressants and who had prominent suicidal ideation, defined as a score of ≥4 on MADRS Item 10. Ninety patients were screened; six were excluded (three for hypertension, one for type 2 diabetes mellitus, two who declined consent), and 84 were randomised to a single intravenous infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The extracted text does not clearly report additional exclusion criteria beyond the brief notes given. Depressive symptoms were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline, 40, 80 and 240 minutes postinfusion, and on Days 2, 3, 5, 7 and 14. Treatment response was defined as ≥50% reduction in MADRS at Day 2 or Day 3. Suicidal ideation was measured with the Columbia–Suicide Severity Rating Scale Ideation Severity Subscale (CSSRS-ISS) at baseline, 240 minutes, and Days 2, 3, 5, 7 and 14; and with the self-reported Positive and Negative Suicide Ideation Inventory (PANSI) at baseline, 240 minutes, and Days 2, 3, 7 and 14. Level of treatment refractoriness was categorised using the Maudsley Staging Method (MSM) as low (≤7), moderate (8–10) or high (≥11). Statistical analysis used generalized estimating equations (GEE) with treatment (ketamine vs midazolam) as a between-patient factor and time as a within-patient factor, including interactions. The investigators also examined the moderating roles of treatment refractoriness (low/moderate vs high), episode duration (<24 vs ≥24 months) and number of failed antidepressants (≤4 vs >4) on symptom trajectories. Given prior evidence that antisuicidal effects may be short-lived, additional analyses restricted to follow-up <7 days were performed. Two-tailed P < .05 was considered significant. Analyses were performed using SPSS version 17.
A c c e p t e d M a n u s c r i p t
Low-dose ketamine infusion had the rapid antidepressant and antisuicidal effects among patients with TRD and prominent suicidal ideation. In addition, the antidepressant effect of ketamine persisted for up to 2 weeks, but the antisuicidal effect lasted only 5 days. Furthermore, timing of ketamine treatment is crucial; specifically, patients with current depressive episodes that have persisted <24 months, or ≤4 failed antidepressant treatments may receive the greatest benefits from low-dose ketamine infusion.
Over the last half century, worldwide suicide rates have increased by 60%, and suicide was accounted for more than 1 million deaths in 2020. The World Health Organization named Taiwan as one of the countries with the highest prevalence (>13/100,000 person-years) of suicide worldwide. The prevalence of suicide in Taiwan peaked inand remained at approximately 16/100,000 person-years from 2012-2019 despite the implementation of the Taiwan Suicide Prevention Program in 2005. A growing body of evidence has supported the rapid and sustained antisuicidal effect of low-dose ketamine. A randomized double-blind placebo-controlled trial of patients with severe suicidal ideation (Scale for Suicidal Ideation score >3) revealed that a greater proportion of patients achieving complete remission in the ketamine group (46 of 83; 63.0%) than in the control group (25 of 73; 31.6%) on Day 3. In this study by, only 40% of participants with severe suicidal ideation were experiencing a major depressive episode, and less than 10% had comorbid dysthymia. The low treatment refractoriness of Abbar et al.'s study patients may partially explain why suicidal ideation remained in remission at Week 6 after ketamine infusion in up to 60% of the participants.reported that the initial antisuicidal effect of a single ketamine infusion diminished rapidly in patients with treatment-resistant depression (TRD), losing efficacy as early as Day 3; however, they reported low baseline scores of suicidal ideation-2.90 ± 0.74 on the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item (Item 10)-which may have affected their results. A meta-analysis of 10 randomized placebocontrolled trials involving 167 patients with major depression, bipolar depression, or posttraumatic stress disorder reported that ketamine rapidly (within 1 day) and significantly reduced suicidal ideation, according to both clinician-administered and self-report outcome measuresA c c e p t e d M a n u s c r i p t; the effect sizes were moderate to large (Cohen's d = .48-.85) at all time points following administration (Days 1-7). In a real-world clinical setting, however, TRD and severe suicidal ideation commonly occur together and exacerbate the effects of one another.a lack of antidepressant and antisuicidal effects after a ketamine infusion of 0.5 mg/kg among patients with TRD and chronic suicidal ideation. Our previous clinical trial revealed that severe treatment refractoriness may affect the therapeutic efficacy of ketamine infusion. Accordingly, optimizing the timing of ketamine infusion is vital, and whether the antidepressant and antisuicidal effects of low-dose ketamine can be generalized to patients with severe TRD and prominent suicidal ideation remains unclear. In current study, we enrolled 84 patients with TRD and prominent suicidal ideation (MADRS item 10 ≥ 4), who were randomized to two groups receiving a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. We followed the patients for 2 weeks to assess their depressive and suicidal symptoms. We hypothesized that the low-dose ketamine infusion would exert rapid and sustained antidepressant and antisuicidal effects in patients with TRD and prominent suicidal ideation, particularly among those without severe treatment refractoriness or chronic TRD.
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Alnefeesi, Y., Chen-Li, D., Jawad, M. Y. et al. · Journal of Psychiatric Research (2022)
Feeney, A., Hock, R. S., Freeman, M. P. et al. · European Neuropsychopharmacology (2021)
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Ionescu, D. F., Bentley, K. H., Eikermann, M. et al. · Journal of Affective Disorders (2019)
Papers in Blossom that reference this study
Gutierrez, G., Kang, M. J. Y., Vasquez, G. · Psychiatry Research (2024)
Of 90 screened patients, 84 were randomised after exclusions; baseline characteristics were similar across groups for age, sex, BMI, age at illness onset, history of suicide attempt and treatment refractoriness, although the midazolam group had slightly higher mean total MADRS scores at baseline (38.26 ± 3.83) than the ketamine group (35.83 ± 4.53, p = .010). Baseline scores for MADRS Item 10, CSSRS-ISS, and PANSI subscales did not differ by group. On the primary outcome of depressive symptoms (MADRS total), GEE models identified a significant antidepressant effect favouring ketamine up to Day 14 (p = .035). Treatment response rates (≥50% reduction on MADRS at Day 2 or Day 3) were greater in the ketamine group (35.7%) than in the midazolam group (11.9%, p = .020). Stratified analyses showed that the antidepressant effect was present in patients with low or moderate treatment refractoriness (p = .004) but not in those with high refractoriness (p = .371). Similarly, benefit was observed particularly among patients whose current depressive episode had lasted <24 months (p = .015) and among those with ≤4 failed antidepressant treatments (p = .023); no significant antidepressant effect was seen in patients with episode duration ≥24 months (p = .329) or >4 failed antidepressants (p = .167). Regarding suicidal outcomes, more patients receiving ketamine achieved full remission of suicidal ideation (CSSRS-ISS = 0) from Day 2 (14 vs 4, p = .015) through Day 5 (11 vs 3, p = .038) compared with midazolam. GEE models indicated significant antisuicidal effects of ketamine measured by CSSRS-ISS (p = .040) and MADRS Item 10 (p = .023) lasting at least to Day 5; however, these clinician-rated effects diminished thereafter. Subgroup analyses mirrored antidepressant findings: antisuicidal benefits were present in low/moderate refractoriness (CSSRS-ISS p = .001; MADRS Item 10 p < .001) but not in high refractoriness. Only patients with episode duration <24 months and ≤4 failed antidepressants derived antisuicidal benefit (CSSRS-ISS p = .042 and p = .027; MADRS Item 10 p = .005 and p < .001, respectively). On self-reported measures, the PANSI negative-suicide-ideation subscale (PANSI-NSI) showed a significant group difference that persisted to Day 7 (p = .039), suggesting reduction in negative suicidal ideation; the PANSI protective-suicide-ideation subscale (PANSI-PSI) did not differ between groups (p = .077). Adverse effects that occurred during infusion and resolved by 80 minutes included derealisation (29 vs 7, p < .001), dizziness (24 vs 5, p < .001) and crying (6 vs 0, p = .026) in ketamine versus midazolam. There were three serious events of attempted suicide requiring hospitalisation: one in the ketamine group (Day 10) and two in the midazolam group (Days 8 and 12).
Su and colleagues interpret their findings as showing that a single low-dose ketamine infusion produced a rapid antidepressant effect that persisted up to 14 days in outpatients with TRD and prominent suicidal ideation, while antisuicidal effects on clinician-rated measures were apparent but attenuated after about 5–7 days. They emphasise that treatment timing and refractoriness moderated outcomes: only patients with low or moderate treatment refractoriness, current episode duration <24 months, or ≤4 prior antidepressant failures benefitted reliably from ketamine. The authors place these results alongside prior studies showing variable durability of ketamine's antisuicidal effect and with previous work identifying number of prior failed treatments and episode duration as predictors of response to other interventions. They note consistency with earlier findings that highly treatment-refractory patients may show limited benefit from ketamine. Su and colleagues also argue that the PANSI results indicate ketamine primarily reduces negative suicidal ideation rather than increasing protective or positive suicidal-coping cognitions. Regarding clinical implications, the investigators propose two recommendations drawn from their data: optimise timing of ketamine treatment in TRD according to disease and treatment course, and consider biweekly infusion for suicide prevention because the antisuicidal effect appears to last only about 5 days. They acknowledge key limitations of the study: ketamine was used as an add-on treatment rather than as a monotherapy, so concomitant medications were not discontinued; only a single infusion was administered, so durability beyond two weeks and effects of repeated dosing were not assessed. The authors therefore call for further studies of repeated low-dose ketamine to evaluate sustained antidepressant and antisuicidal effects in severe depression with suicidal ideation.
Inclusion criteria and study procedure. Adult outpatients aged between 20 and 64 years who were diagnosed with major depressive disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, with inadequate response to at least two different antidepressants with adequate dosage and treatment duration, and had a prominent suicidal ideation were enrolled in current study, and were randomized to two groups receiving a single infusion of either 0.5 mg/kg A c c e p t e d M a n u s c r i p t ketamine or 0.045 mg/kg midazolam. The prominent suicidal ideation was defined by the scores of ≥ 4 at the MADRS item 10 (Montgomery 1980). Depressive symptoms were examined using the MADRS immediately prior to infusion, at 40, 80, and 240 min postinfusion, and sequentially, on Days 2, 3, 5, 7 and 14 postinfusion. Treatment response was defined based on at least one MADRS score of ≥ 50% reduction at Day 2 or Day 3 postinfusion. Suicide symptoms were assessed using the five yes or no questions, including Q1: wish to be dead, Question 2: non-specific suicidal thoughts and Questions 3-5: more specific suicidal thoughts and intent to act, of Columbia-Suicide Severity Rating Scale -Ideation Severity Subscale (CSSRS-ISS) prior to infusion, at 240 min postinfusion, and sequentially, on Days 2, 3, 5, 7 and 14 postinfusion. Suicide symptoms were additionally examined by the selfreported Positive and Negative Suicide Ideation Inventory (PANSI) at baseline, at 240 min postinfusion, and sequentially, on Days 2, 3, 7 and 14 postinfusion. Level of treatment refractoriness was defined by the Maudsley staging method (MSM), and was divided low (≤7), moderate (8-10), and high (≥11)). Exclusion midazolam) as a between-patient factor and time (baseline, infusion, and follow-up) as a withinpatient factor as well as all possible interactions. In addition, we examined the roles of three clinical factors, including treatment refractoriness (low and moderate vs. high), duration of current episode (< 24 vs. ≥ 24 months) and failure numbers of antidepressants (≤ 4 vs. > 4), on the trajectories of above clinical symptoms. Furthermore, owing to the evidence that the duration of the antisuicidal effect of ketamine infusion may not be longer than 1 week, additional analyses with a follow-up duration of < 7 days were performed. Two-tailed P less than .05 was considered statistically significant. All data processing and statistical analyses were performed using SPSS, version 17 (SPSS Inc.).
The study flowchart is shown in the supplementary figure. In all, ninety outpatients with TRD and prominent suicidal ideation were screened; six patients were excluded owing to hypertension (n = 3), type 2 diabetes mellitus (n = 1), and refusal of written informed consent (n = 2). Finally, eighty-four patients were randomly assigned to a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Tableshowed no difference in age (p = .351), sex (p = .634), body mass index (p = .186), age at illness onset (p = .864), history of attempted suicide (p > .738), and treatment refractoriness (p = .788) between two infusion groups. Midazolam group had slightly higher total MADRS scores (38.26 ± 3.83 vs. 35.83 ± 4.53, p = .010) at baseline than ketamine group (Table). The baseline scores of MADRS item 10 (p = .440), CSSRS-ISS (p = .684), PANSI-PSI (p = .746) and PANSI-NSI (p = .549) did not differ between groups (Table). In addition, the psychiatric comorbidities, including posttraumatic stress disorder (p > .999), panic disorder (p > .999) and generalized anxiety disorder (p = .405), did not did not differ between groups (Table). Tableindicated the greater treatment response (35.7% vs. 11.9%, p = .020) in the ketamine group than in the midazolam group. GEE model reported the significant antidepressant effect (p = .035) based on the total MADRS scores up to Day 14 in the ketamine group compared with the midazolam group (Figure). Stratified by the level of treatment refractoriness, the antidepressant effect of lowdose ketamine was noted in patients with moderate and low refractoriness (p = .004) but not in those with high refractoriness (p = .371) (Figure). In addition, the antidepressant effect of ketamine infusion was noted particularly in patients whose current depressive episode had lasted <24 months (p = .015) or in those with ≤4 failed antidepressant treatments (p = .023) (Figure). Patients with current episode > 24 months (p = .329) and those with >4 failed antidepressant treatments (p = .167) did not respond to ketamine infusion (Figure). More numbers of patients receiving ketamine reached full remission of suicidal ideation based on the total CSSRS-ISS score = 0 from Day 2 (n = 14 vs. 4, p = .015) to Day 5 (n = 11 vs. 3, p = .038) compared with those receiving midazolam (Table). GEE models identified the significant antisuicidal effects of low-dose ketamine infusion measured by the CSSRS-ISS (p = .040) and MADRS item 10 (p = .023) at least up to Day 5 (Figure). The antisuicidal effect was noted in patients with moderate and low refractoriness (CSSRS-ISS: p = .001; MADRS item 10: p < .001) but not in those with high refractoriness (p = .383; p = .379) (Figure). Furthermore, only patients whose current depressive episode had lasted <24 months and those with ≤4 failed antidepressant treatments benefited from the antisuicidal effect of ketamine infusion measured by the CSSRS-ISS (p = .042; p = .027) and MADRS item 10 (p = .005; p < .001) (Figure). Figuredemonstrated that the significant antisuicidal effect measured by the PANSI-NSI scores persisted for up to Day 7 (p = .039) between groups. However, the trajectory of PANSI-PSI scores did not differ between ketamine and midazolam groups (p = .077) (Figure). Finally, between (ketamine vs. midazolam)-group adverse effects, including derealization (n = 29 vs. 7, p < .001), dizziness (n = A c c e p t e d M a n u s c r i p t 24 vs. 5, p < .001) and crying (n = 6 vs. 0, p = .026), were noted only during infusion and totally remitted at 80 min postinfusion (Table). Finally, but importantly, there were three serious events of attempted suicide (drug overdose) in our clinical trial: one patient (on Day 10 postinfusion) in the ketamine group and two patients (on Day 8 and Day 12 postinfusion, respectively) in the midazolam group. They were hospitalized for the crisis intervention.
Our results suggest that the antidepressant effect of low-dose ketamine infusion persists for 14 days in patients with TRD and prominent suicidal ideation. However, on the basis of clinician-rated and selfreported measures, the antisuicidal effect of the ketamine infusion may diminish after 5-7 days. Additionally, our study highlights how treatment timing influences the antidepressant and antisuicidal effects of low-dose ketamine; only patients with moderate or low treatment refractoriness, those whose current depressive episode had lasted <24 months, and those with ≤4 failed antidepressant treatments benefited from the low-dose ketamine infusion. Previous studies have investigated the associations between treatment refractoriness and the response to conventional antidepressants, prefrontal theta-burst stimulation (TBS), and electroconvulsive therapy). Fekadu et al. identified the number of prior failed antidepressant treatments, the duration of the current depressive episode, and the severity of depressive symptoms as predictive factors of treatment response to antidepressants). In a study on prefrontal TBS in patients with TRD, only patients with low or moderate treatment refractoriness benefited from 10 sessions of TBS treatment. Furthermore, our previous clinical trial of ketamine versus normal saline infusion in eight patients with TRD and severe treatment refractoriness revealed no antidepressant effect of ketamine). In the present study, we enrolled 41 patients with severe treatment refractoriness and revealed no antidepressant or antisuicidal effects of low-dose ketamine in such patients, corroborating our previous findings. Treatment refractoriness lies on a clinical spectrum; refractoriness may include the failure of three antidepressants to that of all available antidepressants, depressive episodes lasting 6 months to more than 2 years, and response or resistance to neurostimulation). In the present study, only the patients with TRD whose current depressive episode had lasted <24 months and those with ≤4 failed antidepressant treatments benefited from the antidepressant and antisuicidal effects of low-dose ketamine. The antidepressant effect persisted for up to 2 weeks, but the antisuicidal effect lasted only 5 days, supporting the findings of. On the basis of our findings, we propose the following two clinical recommendations. First, clinicians should optimize their timing of low-dose ketamine treatment from patients with TRD on the basis of the disease and treatment course. Specifically, patients experiencing depressive episodes that have persisted ≥12 but <24 months or who have failed to respond to >2 but ≤4 antidepressants may benefit the most from ketamine infusion. Second, our previous study suggested that the symptoms of clinical depression can be ameliorated by biweekly ketamine infusion but that the inflammatory profiles of interleukin-2 and tumor necrosis factor-α may be improved more by weekly infusion). However, for suicide prevention, we suggest biweekly ketamine infusion for patients with TRD and prominent suicidal ideation because the antisuicidal effect persists only 5 days. Our application of the PANSI-PSI and PANSI-NSI may help to clarify the effect of low-dose ketamine on suicidal symptoms. The PANSI-PSI assesses protective factors (i.e., feeling life is worth living, feeling in control of one's own life, and having confidence in future plans) related to suicidal symptoms, whereas the PANSI-NSI examines risk factors (i.e., A c c e p t e d M a n u s c r i p t considering suicide, feeling hopeless, feeling like a failure, feeling lonely or sad, wanting to end the pain) associated with suicidal symptoms. Our findings suggest that the antisuicidal effect of low-dose ketamine infusion is mainly driven by a reduction in negative ideation associated with suicide rather than an increase in positive ideation associated with life. Finally, the inpatient setting was conducted in previous esketamine or ketamine clinical trials of patients with major depressive disorder and suicidal thoughts). In the Murrough et al's clinical trial, study inclusion was initially limited to inpatients (n = 10); the protocol was later changed to enable outpatients (n = 14) in order to improve research feasibility and generalizability. However, we conducted our clinical trial in an outpatient setting with frequent in-person follow-up in the first week (Days 2, 3, 5, and 7). Three serious events of attempted suicide were noted in our clinical trial. Our results may also echo Murrough et al's findings that there was no main effect of setting (outpatient vs. inpatient) and no setting by treatment interaction on ketamine's antisuicidal effect. Our study has several limitations. First, we examined ketamine as an add-on medication, meaning that the other medications used by the patients with TRD were not discontinued during study period. The add-on study design is ethically appropriate for patients with TRD and prominent suicidal ideation and may provide more realistic data. Second, we administered only a single ketamine infusion to each patient. Further studies using repeated infusions of low-dose ketamine are warranted to examine the sustained antidepressant and antisuicidal effects of ketamine in s patients with severe depression and suicidal ideation.
In summary, our study results support the rapid antidepressant and antisuicidal effects of low-dose ketamine infusion on patients with TRD and prominent suicidal ideation. The antidepressant effect of ketamine persisted for up to 2 weeks, but the antisuicidal effect lasted only 5 days. In addition, timing of ketamine treatment is crucial; specifically, patients with moderate or low treatment refractoriness, current depressive episodes that have persisted <24 months, or ≤4 failed antidepressant treatments may receive the greatest benefits from low-dose ketamine infusion.