This double-blind placebo-controlled study study (n=30) with intranasal ketamine (40mg) found significant reductions in suicidal ideation (SI, 80 vs 33% remission) and depressive symptoms (MADRS) 4 hours after administration for those with SI in the emergency department.
Papers cited by this study that are also in Blossom
Ionescu, D. F., Vande Voort, J. L., Niciu, M. J. et al. · Journal of Psychiatric Research (2014)
Background
Suicidal patients often present to the emergency department, where specific anti-suicidal treatment is lacking. Ketamine, a Glutamate modulator and a rapidly acting antidepressant with anti-suicidal properties, might offer relief.
Aims
Evaluation of single, fixed-dosed intranasal ketamine for acute suicidal ideation in the emergency department.
Methods
Between August 2016 and April 2018, 30 eligible suicidal subjects, scheduled for psychiatric hospitalization, independently of their psychiatric diagnosis, were randomized to intranasal ketamine 40 mg or saline placebo. Safety and efficacy evaluations were scheduled for 30, 60, 120, and 240 min post administration and on days 1, 2, 3, 4, 5, 7, 21, and 28. Primary outcome was suicidal ideation.
Results
Fifteen subjects were randomized for each study group. All were analyzed for primary and secondary outcomes. Four hours post administration, the mean difference in suicidal symptoms between the groups, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) item of suicidal thoughts (MADRS-SI), was 1.267 (95% confident interval 0.1-2.43, p < 0.05) favoring treatment. Remission from suicidal ideation was evident in 80% for the ketamine group compared with 33% for the controls (p < 0.05). The mean difference in depressive symptoms, measured by MADRS, at the same time was 9.75 (95% confident interval 0.72-18.79, p < 0.05) favoring ketamine. Treatment was safe and well-tolerated.
Conclusions
Single, fixed-dose, intranasal ketamine alleviated suicidal ideation and improved depressive symptoms four hours post-administration. We present here an innovative paradigm for emergency department management of suicidal individuals. Future larger-scale studies are warranted.
Acute suicidal patients frequently present to emergency departments but lack rapid, specific pharmacological options; these individuals are often hospitalised for short stabilisation and discharged before conventional treatments have time to act. Suicide can cut across diagnostic categories, and a trans-diagnostic framing—treating suicidal ideation as a separable clinical target—may be especially useful in the emergency setting where immediate management is required. Earlier research indicates that ketamine, a glutamatergic modulator with a rapid antidepressant effect, can reduce suicidal ideation for hours to days after administration, and intranasal esketamine has been studied and approved for resistant depression, motivating investigation of intranasal routes for acute suicidality. Domany and colleagues set out to evaluate whether a single fixed dose of intranasal racemic ketamine is feasible, tolerated and efficacious for rapidly reducing acute suicidal ideation in adults presenting to an emergency department who required psychiatric hospitalisation, irrespective of their diagnostic category. The study aimed to test a practical emergency-department intervention (40 mg intranasal ketamine) and to assess suicidal ideation, depressive symptoms, remission rates and safety across a 28-day follow-up period.
This was a randomised, double-blind, placebo-controlled proof-of-concept trial conducted at the University of Cincinnati Medical Center between August 2016 and April 2018. Forty-five patients with suicidal ideation requiring psychiatric hospitalisation were screened and 30 met inclusion criteria and were randomised 1:1 to receive either intranasal racemic ketamine 40 mg or matched saline placebo; 15 subjects were allocated to each arm and all were analysed. Inclusion required age 18–65, BSS first five items score of at least 3 (indicating at least a death wish) and a Columbia-Suicide Severity Rating Scale (C-SSRS) score >2 (active suicidal plans). Exclusion criteria included schizophrenia-spectrum or dissociative disorders, pervasive developmental or cognitive disorders, acute intoxication or withdrawal, homicidal risk, pregnancy/breastfeeding, hypersensitivity to ketamine and significant medical conditions that would contraindicate ketamine. Randomisation and blinding were maintained by having the pharmacist prepare syringes; the pharmacist was the only non-blinded person. Investigators originally planned IV weight-based dosing but switched to a fixed intranasal dose for practicality and based on reported intranasal bioavailability (~45%); the chosen dose was 40 mg delivered via a mucosal atomisation device as four 0.1 ml squirts (10 mg each) across both nostrils with a 10-minute separation. Vital signs were monitored for four hours post administration, after which participants were admitted to psychiatric units; discharge decisions were made by a blinded non-study physician. Treating clinicians provided standard psychiatric care and could change treatments as clinically indicated. Primary outcome was change in suicidal ideation over four weeks assessed with both a self-report (Beck Scale for Suicidal Ideation, BSS) and a rater-based single item from the Montgomery–Åsberg Depression Rating Scale (MADRS-SI). Assessments occurred at baseline, 30, 60, 120 and 240 minutes post-administration and on days 1, 2, 3, 4, 5, 7, 14, 21 and 28. Secondary outcomes included change in depressive symptoms (MADRS), remission from suicidal ideation (MADRS-SI = 0), length of hospitalisation and harms. Side effects were recorded using a Ketamine Side Effects Scale (KSES). Data were collected in REDCap. Statistical analyses used SPSS with two-sided tests at alpha = 0.05; normality checks were applied. Linear mixed models were used for group-by-time comparisons, while 4-hour outcomes were analysed with independent t-tests; remission rates used chi-square and length of stay used Mann–Whitney U. The trial had been planned for n = 60 but recruitment was terminated early after the principal investigator left the institution.
Acute suicidal patients represent more than half a million annual admissions to emergency departments in the U.S. In the absence of specific treatment for acute suicidal ideation, these patients are often hospitalized for brief stabilization and later discharged before psychopharmacological treatments can show efficacy. Although suicide is frequently associated with depression, it may be mediated by a general psychopathology dimension, and can be considered as a distinct, "trans-diagnostic" entity, independent of other psychiatric diagnosis. Transdiagnostic approach can be useful in the emergency department, where suicidal patients need to be rapidly managed, sometimes prior to establishing a thorough diagnosis. Ketamine: A glutamatergic modulator, has been shown to rapidly improve depressive symptoms in unipolar, and bipolar depression, and Esketamine the S-enantiomer of ketamine, was recently approved by the FDA as a treatment for resistant depression. The rapid antidepressant effect of ketamine makes it a promising treatment option for suicidal ideation both in unipolar, and bipolar depression. A recent meta-analysisfound it to reduce suicidal ideation up to 72 hours post infusion. Esketamine was also studied for the rapid reduction of suicidal ideation for depressed subjects with imminent suicide riskwith mixed results. Furthermore, the rapid anti-suicidal effect of ketamine makes it a promising treatment option for emergency department interventions. This was studied byin a small open trial,who reported a significant reduction in suicidal ideation but failed to reach their preset goal of a Scale for Suicidal Ideation (SSI)<4. Another small (n ¼ 10) controlled study,, found a significant reduction of suicidal ideation four hours post infusion, and concluded that ketamine may be an effective means of acutely improving suicidal ideation and depression. In our previous pilot study, subjects with depression and acute suicidal ideation who presented to the emergency department, were randomized to intravenous ketamine or control. Our preliminary results showed a reduction in suicidal ideation two hours post ketamine infusion. Additionally, in accordance with the trans-diagnostic approach, it was suggested that ketamine's anti-suicidal properties may not be entirely driven by improvement in depressive symptoms.
Create a free account to open full-text PDFs.
Ballard, E. D., Luckenbaugh, D. A., Walls, T. S. et al. · Journal of Psychiatric Research (2015)
Burger, J., Capobianco, M., Lovern, R. et al. · Military Medicine (2016)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Huggins, C., Glue, P., Martin, D. et al. · Journal of Psychopharmacology (2018)
Grunebaum, M. F., Ellis, S. P., Keilp, J. G. et al. · Bipolar Disorders (2017)
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J. et al. · Bipolar Disorders (2014)
Short, B., Fong, J., Galvez, V. et al. · Lancet Psychiatry (2017)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
Wilkinson, S. T., Ballard, E. D., Bloch, M. H. et al. · American Journal of Psychiatry (2017)
Papers in Blossom that reference this study
Shivanekar, S., Pizon, A., Spotts, C. et al. · International Journal of Environmental Research and Public Health (2022)
Gaither, R., Ranney, M., Mha, A. P. et al. · JACEP (2022)
Thirty participants were randomised and there were no reported baseline differences between groups on demographics or baseline scores (MADRS, MADRS-SI, BSS) in the extracted text. All randomised subjects (15 per arm) were included in analyses. At four hours post administration the rater-based MADRS-SI showed a statistically significant advantage for ketamine: mean difference 1.267 (ketamine group reduction 4.89 ± 0.4 versus placebo 3.35 ± 0.5), 95% CI 0.1–2.43, p < 0.05. The self-reported BSS showed a larger numerical reduction in the ketamine arm (17.4 ± 9.4) than placebo (10.5 ± 8.21) but this did not reach statistical significance (p = 0.086). A linear mixed model for group-by-time interaction did not reach significance. Remission of suicidal ideation (MADRS-SI = 0) at four hours occurred in 12/15 (80%) of ketamine-treated subjects versus 5/15 (33%) of controls (p < 0.01). Depressive symptoms measured by MADRS at four hours favoured ketamine with a mean difference of 9.75 (95% CI 0.72–18.79, p < 0.05). Length of hospitalisation showed a non-significant trend favouring ketamine: median 5 days (25th–75th percentiles 4–8.5) versus 9 days (5.5–10.5) for placebo (p = 0.089). Safety assessments indicated more side effects in the ketamine group at one hour post dose on the KSES, but differences were not statistically significant; by two hours there was no evidence of side effects. No participants developed psychotic symptoms. One participant with baseline dissociative symptoms reported worsening dissociation but also reported overall improvement in suicidal measures. The authors note the study is underpowered for definitive safety conclusions.
Domany and colleagues interpret their findings as supporting that a single fixed 40 mg intranasal dose of ketamine can reduce suicidal ideation and improve depressive symptoms within four hours in a trans-diagnostic cohort presenting to an emergency department, and that the intervention induced remission in a substantial proportion of participants. They position the results as consistent with prior ketamine work in both emergency and non-emergency contexts and suggest intranasal administration may offer a pragmatic, potentially safer route than intravenous delivery. The investigators emphasise that the trial has limitations that temper conclusions: recruitment was terminated early yielding a small sample, the linear mixed model did not detect a significant group-by-time interaction, and effective masking is difficult in ketamine trials because of its psychomimetic and cardiovascular effects; the absence of an active placebo is noted. They also acknowledge lack of blood ketamine levels and that post-intervention psychotropic treatments were not recorded in the extracted text, which limits interpretation of durability and dosing adequacy. A notable observation was the sustained low suicidal-ideation scores in the ketamine arm over the 28-day follow-up, but the authors caution this may reflect inpatient support and is not conclusive given the study’s limited power. Clinical implications discussed by the authors include the potential for rapid symptom relief to influence immediate risk management, possibly reducing need or duration of hospitalisation and easing emergency department loads; nevertheless they call the observations preliminary. The study team recommends larger, adequately powered trials with improved blinding strategies (for example an active comparator), blood-level monitoring and careful recording of subsequent treatments, as well as consideration of ambulatory pathways to manage the sub-acute period after an emergency intervention.
The authors conclude that single fixed-dose intranasal ketamine was feasible and appeared safe in this emergency-department, trans-diagnostic sample and produced rapid reductions in suicidal ideation and depressive symptoms at four hours, including higher remission rates and a trend toward shorter hospital stays. They stress the results are inconclusive because the trial was underpowered and a linear mixed model did not demonstrate a significant group-by-time effect. Domany and colleagues recommend larger-scale studies to establish whether this paradigm can be recommended for acute management of suicidal patients.
Ketamine was traditionally administered intravenously. Other routes of administrations (e.g., oral, subcutaneous, intramuscular, and intranasal)have been less studied, and have been reported to be safer with less psychomimetic and cardiovascular side effects (36% compared with 72%) though of lesser efficacy (40% vs 60% response rate, at 24 h). Alternatively, a small trial reportedsimilar efficacy and side effects between IV, IM, and SC administration of ketamine. The bioavailability of nasal ketamine spray is reported to be approximately 45%and is greater than sublingual, rectal, or oral administration. Esketamine, as mention earlier, was administered intranasally,and a commercial device was announced. As a next step of our pilot studywe aimed to evaluate intranasal administration, which is a more practical route of administration and can be used as an emergency intervention. Furthermore, our patients were recruited based on theirsuicidal ideation and intent independently of their psychiatric diagnosis meaning that, for example, no diagnosis of depression was required. Objectives: Evaluation of the feasibility, tolerability, and efficacy of a single, fixeddose of intranasal ketamine for alleviation of acute suicidal ideation in trans-diagnostic extremely suicidal patients in an emergency department setting, independent of their diagnosis.
Forty-five subjects, with suicidal ideation in need of psychiatric hospitalization were evaluated in the Emergency Department of the University of Cincinnati Medical Center (UCMC) between August 2016 and April 2018 and were assessed for study eligibility. Fifteen subjects were ruled out due to medical or psychiatric exclusion criteria. Thirty subjects were allocated for randomization. Subjects were included if they required psychiatric hospitalization due to suicidal risk and suffered suicidal ideation with a cutoff score of at least three on the first five items on the Beck Scale for Suicidal Ideation (BSS)meaning at least a death wish; and a score higher than 2 on the Columbia Scale for Suicide Severity Rating (C-SSRS) (since last visit, version 1/14/ 09), meaning at least the presence of active suicidal plans. All participants were evaluated by the primary clinical team prior to contact by study personnel and admission criteria was determined by a treating (non-study) clinician. Participants were age 18-65, with no genders, racial nor ethnic exclusions. Participants were excluded if they were diagnosed with schizophrenia spectrum disorders, dissociative disorders, pervasive developmental disorder or cognitive disorder. Acute intoxication or withdrawal from alcohol or other substances, as determined by clinical interview and urine drug screen were also excluded. Homicidal risk as determined by clinical interview was excluded. Pregnant, lactating or post-partum women (within 2 months of delivery) were excluded; all women of reproductive potential had a negative urine pregnancy test. Subjects were excluded if they had any known hypersensitivity or history of a serious adverse reaction to ketamine and if they had suffered any clinically significant medical condition that would preclude the use of ketamine, including respiratory illness requiring the regular use of oxygen.
This study was reviewed and approved by the University of Cincinnati Institutional Review Board and registered with clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT02183272). Written informed consent was obtained from all participants after a thorough description of the study and prior to any study-specific procedure. Baseline assessments included physical examination, a full medical and psychiatric history, and urine obtained for drug screen and pregnancy test for women of reproductive potential. Prior to subjects' consent, the pharmacist, the only non-blinded member of the study group, prepared active drug and placebo in similar 10 ml syringes following a randomization schedule. Those meeting all inclusion and no exclusion criteria were randomized (1:1) to racemic ketamine 100 mg/ml 40 mg (0.4 ml) or matched inactive placebo (normal saline). Originally, we intended to administer weight-based ketamine intravenously with a dose of 0.2 mg/kg, as reported in clinicalTrials.gov. However, the first reports of intranasal administrationlead us to evaluate this more practical way of administration, and to simplify dosing we investigated fixed-dosing, considering a bioavailability of 45%, the calculated dose (based on average human weight of 80 kg) was 40 mg. An intranasal mucosal atomization device was used to provide one intranasal application of solution (volume 0.1 ml) in each nostril and an additional squirt in each nostril separated by 10 minutes, (altogether 4 squirts). Each of the 4 ketamine squirts provided 10 mg of study drug, totaling 40 mg. Drug was applied by the study physician-a psychiatrist. Subjects' vital signs were monitored for 4 hours post administration. At the completion of the post-treatment observation period, the participant was admitted to the psychiatry units at the UCMC. The time of discharge was determined by a blinded, non-study physician who was not aware of the patient's status (randomization) in the study. All patients received standard psychiatric care by the treating (non-study) psychiatrist. The treating physicians could make any changes in treatment they deemed warranted by the patient's condition.
The primary outcome was change in suicidal ideation over a 4-week period. As this was a proof-of-concept trial no a-priori timepoint was chosen as a specific primary outcome measure. Further we chose to observe both rater-based and patient-reported-scales; Beck Scale for Suicide ideation (BSS) and the suicidal thoughts item on the Montgomery Åsberg Depression Rating Scale (MADRS)-(MADRS-SI), respectively. Assessments were performed at baseline prior to treatment and at 30, 60, 120 and 240 min post-administration, and on days 1, 2, 3, 4, 5, 7, 14, 21 and 28 post-administration.
Baseline suicidal ideation, intensity of ideation, and suicidal behaviors were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), (Since last visit, version 1/ 14/09). The C-SSRS is a widely used and valid scale used to assess both recent and lifetime suicide-related thoughts and behaviors. Additional evaluation of baseline suicidal ideation was performed using the Beck Scale for Suicidal ideation (BSS). This scale is the self-reported version of the more prevelent Scale for Suicide Ideation (SSI) and has been shown to be prospectively associated with suicidal behavior including death by suicide., and the suicidal thoughts item on the Montgomery Åsberg Depression Rating Scale (MADRS)-(MADRS-SI). The MADRS is a valid, widely used, questionnaire for depression (see below) and the MADRS-SI-suicidal thoughts-(graded 0-6) is an overall clinician-rated global impression of suicidal thoughts and actions. Change in suicidal ideation was evaluated using the BSS scale. This scale, however, has some limitations with interpretation of the changes over time. Most notably because the structure of the scale dictates that the scale changes depending on the patient's responses to the first five questions; if the answers to questions 4 and 5 are zero (which assess approach toward death), the other 14 questions are not asked. This changes the possible total score of the scale significantly. Further issues with the BSS are that it conflates trait and state factors, with many questions not able to change imminently or at all. The second scale for change in suicidal ideation was the suicidal thoughts item on the (MADRS)-The (MADRS-SI). This question has been used in many studies of treatment effects on suicidal behavior, including rapidly acting anti-suicidal treatments, and has been validated for those trials.
Secondary outcomes were changes in depressive symptoms, remission from suicidal ideation, days of admission, and harms.
The MADRSwas the measure of change in depression. The MADRS is a commonly used and reliable clinician-rated assessment of depression severity that is sensitive to treatment effects. It has been used successfully in prior ketamine studiesThe MADRS has been modified to reflect the period since last assessment. Remission from suicidal ideation was defined by a score of 0 on the MADRS-SI item (indicating no suicidal thoughts).
This outcome reflects a broad clinical evaluation, risk assessments, and especially, suicidality evaluation. Additionally, this outcome holds public health significance, with economic implications. Time of discharge (which determined this outcome) was decided by a non-study physician, who was blinded to the randomization.
Currently the assessments of side effects in ketamine trials for depression is inadequate. Therefore, we have developed a Ketamine Side Effects Scale (KSES), a similar version of the recently published, Ketamine Side Effect Tool (KSET), to assess for ketamine side effects. In this scale, we evaluated vital sign abnormalities, agitation, sedation, dizziness, nausea, psychosis and dissociation in a concise manner (scales of 0-5).
To ensure the quality of Electronic Data Capture (EDC) and management, the data management team used the REDCap EDC system. REDCap provides a process for building a database, an interface for collecting data, data validation, and automated export procedures for data downloads to statistical packages (SPSS).
All outcomes were summarized descriptively (e.g., frequencies, summary statistics) and assessed for normality prior to analysis using normal probability plots and Kolmogorov Smirnov tests. All tests were two-sided and considered statistically significant at alpha¼.05. All analyses were performed using SPSS. This study was planned, built and powered for a larger sample size (n ¼ 60). However, because the primary investigator has left the institution, we had to prematurely end study recruitment. Baseline demographic characteristics such as age and gender were compared using chi-square or t-test. Comparison of the two groups for suicidal ideation and depressive symptoms at several intervals post-administration was calculated using linear mixed models. In addition, data at four hours post-administration was analyzed using t-tests for independent samples. Remission rates were calculated using Chi square. Median length of hospitalization was reported with 25th and 75th percentiles, and statistics calculations used the Mann Whitney U-test. Tolerability and safety were evaluated descriptively and separately for each treatment group and compared using chi-square or t-test.
Demographic characteristics and mean baseline scores on the MADRS, MADRS-SI, and the BSS of recruited subjects are presented in Table. Fifteen subjects were randomized to the ketamine group and 15 to the placebo group. All were analyzed for primary and secondary outcomes. There were no differences between groups at baseline in any of the demographic or assessment scales. The main outcome measure was change in suicidal ideation, as measured by the self-reported BSS and rater-based MADRS-SI. Additional outcomes were remission from suicidal ideation as indicated by MADRS-SI ¼ 0, total days of admission, and a change in depression as measured by the MADRS. This trial was prematurely ended because the primary investigator has left the institution.
Four hours post drug administration; we found a reduction in suicidal ideation. The mean difference in suicidal symptoms between the groups, measured by the MADRS-SI (scale of 0-6), was 1.267 (Reduction of 4.89 ± 0.4 compares with 3.35 ± 0.5) (95% confident interval 0.1-2.43, p < 0.05) favoring treatment. In the self-reported BSS scale (full version), we observed a reduction of 17.4 ± 9.4 points in the ketamine group compared to a reduction of 10.5 ± 8.21 in the placebo group. This reduction, however, did not reach a statistically significant level (p ¼ 0.086). Furthermore, linear mixed model did not show significance for the group by time interaction. Unexpectedly, the suicidal ideation score for the ketamine group remained low for the entire study trial following a single ketamine administration. See Figurefor mean suicidal score across time. Figure: self reported BSS, and Figure. rater based MADRS-SI.
Remission from suicidal ideation was defined by a score of 0 on the MADRS-SI item (indicating no suicidal thoughts). Four hours post-administration, twelve of 15 subjects in the ketamine group achieved remission (80%) compared to 5 of 15 (33%) in the placebo group (p < 0.01). Depression: The mean difference in depressive symptoms, measured by MADRS, at 4 hours was 9.75 (95% Confidence Interval 0.72-18.79, p < 0.05) favoring the ketamine group. See Figurefor the change in depressive symptoms across time as apparent from the MADRS. Length of hospitalization: The ketamine group had median hospitalization length of 5 days (4-8.5) compared with 9 days (5.5-10.5) for the control (median is reported with 25th and 75th percentiles). There was a trend toward the effect of ketamine on the reduction of admission length (p ¼ 0.089). See Figure.
We evaluated the harms throughout the study period. Side effects were most prominent one-hour post administration and the results of the KSES at one hour are presented in Table. The ketamine group reported a higher prevalence of side effects; however, no statistically significant difference was noted. Two hours post administration; no evidence of side effects were found. No subject suffered psychotic symptoms. This observation may be, in part, due to the relatively low bioavailability of intranasal administration (45%). One subject, who had baseline dissociative symptoms, reported worsening of those symptoms; however overall, this subject reported a good experience, and his suicidal scales improved.
We found single, fixed-dose intranasal ketamine to alleviate acute suicidal ideation and improve depressive symptoms four hours post administration in a trans-diagnostic, extremely suicidal cohort presenting to the emergency department. Further, we found ketamine to induce remission of suicidal ideation in 80% of our study subjects, and we report a trend toward the effect of ketamine in shortening the length of hospitalization.
Our study replicated the results of emergency department settings of Burger et al., and of our pilot studyin a larger cohort. Further, our findings are consistent with others who demonstrated the anti-suicidal Side effects 1 h post administration Evaluation was conducted on the Ketamine side effect scale For each side effect there is a 0-5 scale 0-None, 1-mild, 2-moderate, 3-marked, 4-severe, 5-very severe discontinue and consider intervention. For increase in systolic blood pressure the scale for was: 1-<10 mmHg, 2-10-20 mmHg 3-20-30 mmHg, 4 À 40-50 mmHg, 5->50 mmHg For increase in pulse the scale was: 1-<5bpm, 2-5-10 bpm, 3-10-15 bpm, 4-15-20 bpm, 5->20 bpm. effect in a non-emergency context in treatment resistant depression, bipolar depressionand on a wider diagnostic cohort. In our previous study, we demonstrated the anti-suicidal effect of a single intravenous infusion of ketamine; here, we administered ketamine intranasally; which potentially can be safer and more practical. Our study is similar in design to the study ofwith two main differences. The first is that they studied Esketamine, and the second is our transdiagnostic approach. The similar results, however, emphasis the replicability of the data and strengthen both studies. Fixed 100 mg dose intranasal administration of ketamine for treatment resistant depression was evaluated by Galvez et albut they had to suspend their trial due to tolerability problems. Our study was designed to assess ketamine for suicidal ideation, and we used lower doses (40 mg compared to 100 mg). Both of the studies used fixed-dose and not the traditional weight-based dose (usually 0.5 mg/kg). Compared to Galvez et al, all of our subjects tolerated this route of administration well, we found it to be pragmatic and applicable for clinical settings.
Suicide is highly related to depression; however, it might also be a devastating result of many different mental disorders or life adversities.described that the improvement in suicidal ideation following ketamine infusion, is related, but not completely driven by improvement in depression and anxiety. Hoertel et al in a national prospective studyargued that suicide attempts are related to a general psychopathology dimension. This approach was strengthened by the DSM5 proposed criteria of "Suicidal behavior disorder". Further, suicide, as a distinct entity, was supported by Niculescu et alwho reported specific blood biomarkers for suicidality, and additional studyreported a neural presentation of suicide. A trans-diagnostic approach to the management of suicidal ideation is particularly useful in the emergency department settings, in which a potentially life-threatening condition requires an immediate reaction, sometimes prior to a comprehensive diagnosis.
Few treatment options for suicide ideation are available, including lithium, clozapine, electro-convulsive treatment (ECT), and psychotherapies such as cognitive behavioral treatment (CBT) or dialectical behavioral treatment (DBT). Those treatment options lack the desired rapid effect.. Since suicidal ideation often occurs in the context of depression, another widely used approach is prescribing antidepressants. which are sub-optimal for the management of acute suicidal ideation, because of the time lag until full efficacy, and that substantial portion of the patients which will fail to achieve remission. Further, antidepressants can paradoxically, enhance suicidal thoughts, especially in young adults and adolescents. Therefore, there is an urgent need for rapidly effective strategies to reduce suicidal ideation. The importance of this study is the proposal of a novel paradigm to the management of acute suicidal ideation in the emergency department settings, one that includes diagnostic considerations-a trans-diagnostic approach, and treatment option-a single, fixed-dose intranasal ketamine.
We found that ketamine alleviated suicidal thoughts, and depressive symptoms four hours post administration. Although promising, our observation is inconclusive, and the linear mixed statistical model did not show significance for the random group by time interaction. Suicidal ideation can be brief and transient, thus even temporary relief, as was seen by the reduction in suicidal ideation 4 hours post-treatment in our study, can have a crucial effect on morbidity and mortality. Another potential outcome of this might be a reduction in patient load in emergency departments; instead, some of the patients in question might be referred for treatment in an ambulatory clinic given the reduction in the severity of their suicidal symptoms. In order to fully assess the clinical advantages, one should consider two additional questions; the first is remission from suicidal ideation. This binary measure is important in order to evaluate the management of suicidal patients, meaning hospitalization or discharge. We defined remission as a score of 0 on the MADRS-SI item (indicating no suicidal thoughts). We found that four hours post infusion, 80% of the subjects in the ketamine group achieved remission compared to 33% in the placebo group (p < 0.01). which could potentially lead to fewer hospitalizations. The other relevant measure is the length of hospitalization. An intervention that can shorten the length of hospitalization, may improve satisfaction and quality of life for patients and will have great clinical and economical value. We showed a trend toward shortening the length of hospitalization. The ketamine group had a median four days of hospitalization fewer than the control group; 5 days (4-8.5) compared with 9 days (5.5-10.5), (Percentiles 25 and 75 are additionally reported, p ¼ 0.089). See Figure. To conclude; the clinical implication of our observation -a temporary relief of suicidal ideation is yet to be determained, and further studies, with longer follow-up and outcome-oriented measures are warranted to establish wellgrounded evidence on the anti-suicidal effect of ketamine, and in any case further steps are needed in order to embrace this treatment paradigm, such as establishment of ambulatory settings for the sub-acute period following the treatment effect. Unexpectedly, we found that suicidal ideation did not relapse. The relatively extended follow-up of 28 days was designed to assess safety; however, we were surprised to learn that the rates of suicidal ideation stayed low. While no statistically significant group by time interaction was noted, this observation, which was similarly reported by, can be partly explained by the safety and support provided in inpatient units, and deserves consideration for future studies; including a study design with the power to evaluate this unexpected observation. We found this treatment safe; however, this study is underpowered to draw safety results conclusively. Given the lack of acute treatment for suicide ideation and the lack of serious adverse events, the use of ketamine for acutely suicidal individuals deserves serious considerations. While the large placebo effect, described here and in other ketamine studies, can disguise of the anti-suicidal effect of ketamine, it's important to consider that the placebo effect in our study should be viewed as treatment-as-usual, which encompassed admission to a psychiatric ward including biological and psychological treatments as well as social interventions. In addition, the placebo effect is an example of the observer effect (the mere observation of a phenomenon inevitably changes the phenomenon). In this case, measurement of suicidal ideation, can have empathic virtue which can reduce suicidal thoughts.
The main limitation of this study is the small sample size, caused by early termination of recruitment (as described in the methods section). Second, effective masking is an inherent problem in all ketamine studies due to ketamine's rapid psychomimetic effects. An active placebo, such as midazolammight have better preserved the blindness. On the other hand, active placebo may offer relief from anxiety and might cause a different bias (type 2 error). Another obstacle for blindness might have been the cardiovascular effect, (i.e., elevation of blood pressure and/or pulse rate) which can be apparent to raters and subjects alike. Future studies should consider prescribing active placebo and using different efficacy and safety raters to maintain proper masking. An additional limitation was the lack of blood ketamine levels. The bioavailability of Intranasal administration of ketamine is approximately 45%. This could account for the low side-effects rate and the inconclusiveness of the efficacy results. Blood ketamine levels could determine whether subjects achieved appropriate dosing and that administration of ketamine was successful. Following the study intervention, we did not evaluate additional psychotropic medications or other interventions. Although, those interventions can be controlled using randomization it would have been preferable to record and report any difference between the groups.
Single fixed-dose intranasal ketamine was found to be a safe and feasible treatment option in the emergency department settings for a trans-diagnostic cohort with acute suicidal thoughts, in need of hospitalization. We found it to alleviate suicidal ideation four hours post administration, induce remission, and found a trend toward shortening the length of hospitalization. However, our results are inconclusive, and a linear mixed model failed to detect significance for the group by time interaction. We present here a novel paradigm including diagnostic considerations: a trans-diagnostic approach, and a treatment option-a single, fixed-dose of intranasal ketamine. Future larger-scale studies are warranted based on this approach to establish treatment recommendations for the acute management of suicidal patients.