Is Ketamine Efficacious for Rapid Treatment of Acute Suicidal Ideation in an Emergency Setting? Lessons Learned from A Pilot Randomized Controlled Trial

Is Ketamine Efficacious for Rapid Treatment of Acute Suicidal Ideation in an Emergency Setting? 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Lessons Learned from A Pilot Randomized Controlled Trial Maryam Barzkar, Kaveh Alavi, Kazem Malakouti, Mohamad-Amin Khajeh-Azad, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4718815/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Feb, 2025 Read the published version in BMC Research Notes → Version 1 posted 15 You are reading this latest preprint version Abstract Background Ketamine has emerged as a promising agent for the rapid reduction of suicidal thoughts. However, its efficacy across a broader spectrum of psychiatric disorders remains underexplored. Objective This study aimed to evaluate the efficacy of a single infusion of ketamine in inducing rapid remission of severe suicidal ideation, compared to Midazolam, in a population with acute suicidal thoughts. Methods In a double-blind randomized controlled trial conducted in Tehran, Iran, from January to July 2022 (IRCT20220118053756N1), 36 inpatients with acute severe suicidal ideation were enrolled. Participants were randomly assigned to receive either a single dose of ketamine (0.5 mg/kg) or Midazolam (0.02 mg/kg). Suicidality was assessed using the Beck Scale for Suicide Ideation (BSSI) and the Suicide-Visual Analog Scale (S-VAS) before the intervention and at 12 and 24 hours post-administration. Results At baseline, the Midazolam group exhibited significantly higher BSSI scores and a higher rate of borderline personality disorder than the Ketamine group. Mean BSSI and S-VAS scores at 12 and 24 hours after the treatment in both groups. Despite these observations, no statistically significant differences were found between the groups in terms of BSSI and S-VAS scores. Conclusions The findings suggest that ketamine may reduce suicidal ideation, but its efficacy varies by psychiatric diagnosis. The groups were not significantly different in the main study outcomes. Suicide Ketamine Midazolam N-methyl-d-aspartate receptor antagonist Depressive Disorder Figures Figure 1 Background Suicide causes a total of about 700,000 annual deaths globally( 1 ). The World Health Organization (WHO) has identified suicide as a priority condition in the Mental Health Gap Action Programme (mhGAP) launched in 2008( 2 ). The mhGAP aims to scale up services for mental, neurological, and substance use disorders in low- and middle-income countries( 2 ). The WHO Mental Health Action Plan 2013–2030 has set a global target of reducing the suicide rate in countries by one-third by 2030( 2 ). Suicidal ideation, especially when severe, is considered a medical emergency( 3 ). Although antidepressants reduce suicidal ideation by controlling other symptoms of depression, their optimal clinical effects usually take weeks to months( 4 ). Ketamine at subanesthetic doses is the only FDA-approved antidepressant with its onset of action within a few hours( 5 ). Ketamine has also been investigated for its rapid effects on reducing suicidal thoughts independent of its antidepressant effect( 6 – 8 ). Numerous studies have shown that the rapid antidepressant effect of ketamine in depression can reduce suicidal thoughts in patients with major depressive disorder with suicidal ideation( 9 ). However, the efficacy may vary in different patients based on their diagnosis and further trials are needed to assess its safety and efficacy across psychiatric diagnoses and settings( 9 ). Objectives We aimed to compare the anti-suicidal effects of Ketamine infusion to Midazolam for rapid remediation of acute suicidal thoughts in patients admitted to the hospital with severe suicidal ideation. Methods Setting, Participants, and Design This double-blind randomized controlled trial was approved by the ethics committee of Iran University of Medical Sciences (Ethics reference number: IR.IUMS.FMD.REC.1399.069) and registered in the Iranian Registry of Clinical Trials (IRCT20220118053756N1). It was conducted from January to July 2022 at two university hospitals in Tehran, Iran. Patients aged 18–65 with acute suicidal ideation associated with major depression were recruited. Written informed consent was obtained from patients and their legal guardians prior to enrollment. Acute suicidal thoughts were defined as thoughts starting within 72 hours before admission, associated with serious risk, and requiring psychiatric hospitalization. Thirty-six patients meeting the inclusion criteria were enrolled via convenience sampling and randomized to receive either a single-dose ketamine or midazolam infusion. Exclusion criteria included physical disorders (thyroid disorder, diabetes, hypertension, stroke, brain surgery, neurological disorders, seizures), allergy to ketamine or midazolam, pregnancy, and lactation. Patients taking antidepressants regularly in the previous month were also excluded. The effect was evaluated using the suicide visual analog scale (S-VAS) and Beck Suicide Severity Inventory (BSSI) at baseline, 12 hours (10–14 hours), and 24 hours after administering the medication (22–26 hours). Randomization, Allocation Concealment, and Blinding One researcher coded Ketamine and Midazolam as A and B. The second researcher who was unaware of the coding created a blocked random sequence of A and B using a computer-generated list of random numbers. The same researcher maintained the list. The recruiting researcher was unaware of the patient group at the time of assignment and would contact the second researcher to inquire the patient assignment. Midazolam and Ketamine were prepared in packages with the same appearance and labeled as A and B. To prevent the sedative effects of Midazolam altering the masking, Midazolam was administered at a low non-sedative dose. Interventions The patients received either a single dose of Ketamine hydrochloride (Exir Pharmaceutical Company, Iran) infusion 0.5 mg/kg or Midazolam(Daroo Pakhsh Co. Iran) 0.02 mg/kg infusion in 100 cc sodium chloride 0.9% over 40 minutes. The patient’s blood pressure, level of consciousness, and blood oxygen saturation, heart and breathing rate during the injection were monitored throughout the infusion. Either a physician or a highly skilled anesthetist was stand-by at the participant’s bedside throughout the infusion to handle emergency tracheal intubation or cardiopulmonary resuscitation if required. Outcome Measurement A psychiatrist, who was blinded to the intervention, interviewed all participants before, 12 hours after, and 24 hours after administration of the medication, and filled Hamilton’s scale and BSSI. The same outcome assessor explained the protocol and administered the S-VAS to the participants. The main outcomes were suicidal ideation and the secondary outcome was the severity of depression. Hamilton's scale: Hamilton’s scale measures the severity of depression through 17 questions encompassing symptoms of depression including mood, guilt, sleep pattern, and suicidal thoughts. Scores above 22 point to very severe depression( 10 , 11 ) Beck Scale for Suicidal Ideation: The Beck scale for suicidal ideation (BSSI) consists of 19 items that assess suicidality in detail. The score obtained from BSSI ranges from 0 to 38; the higher the score, the more severe the suicidal thoughts ( 15 – 17 ). The Persian version of this instrument has also been deemed valid and reliable( 12 ). S-VAS (Suicide visual analog scale): The Visual Analogue Scale, a method for measuring the severity of an experience subjectively, has been standardized and widely used for assessing suicidal ideation ( 18 ). Statistical methods The obtained data were analyzed by SPSS-26 software. Repeated measures ​​analysis of variance (ANOVA) was used except for the change in VAS before treatment and 12 hours post-treatment in the midazolam group. In all cases, p < 0.05 was considered significant. Results Baseline Characteristics A total of 36 patients were randomized 1:1 to the study groups (Fig. 1). Other baseline characteristics are shown in Table 1 . Except for borderline personality disorder(BPD), there was no difference between the two groups. The severity of suicidal thoughts based on BSSI scores was higher in the midazolam group than in the ketamine group at the beginning of the study (Table 1 ). Table 1 Table of Baseline Characteristics of Trial Participants Participant Characteristics Categories Midazolam Number(percent) Ketamine Number(percent) Gender Man 10(55.5) 13(72.2) Marital Status Single 11(61.1) 10(55.6) Married 5(27.8) 7(38.9) Divorced 2( 11 ) 1(5.6) Occupational Status Employed 11(61) 9(50) Education Below high school diploma 4(23.2) 1(5.6) High school diploma 8(44.4) 8(44.4) University education 6(33.3) 9(50) Personal History Admission in psychiatric hospitals 14(77.8) 14(77.8) Suicidal attempt 13(72.2) 8(44.4) Borderline personality disorder 13(72.2) 6(33.3) Substance use disorder 10(55.6) 6(33.3) Family history of Mood disorders 15(83.3) 13(72.2) Suicidal attempt 8(44.4) 5(27.8) Current Diagnosis Major Depressive Disorder 5(27.8) 8(44.4) Bipolar Disorder-I Depressive Episode 0 1(5.6) Bipolar Disorder-I Manic Episode 2(11.1) 4(22.2) Personality Disorder 10(55.6) 3(16.7) Anxiety Disorders/ Obsessive Compulsive Disorder 1(5.6) 2(11.1) Psychiatric comorbidities Major Depressive Disorder 1(5.6 1(5.6) Obsessive Compulsive Disorder 0 2(11.1) Other Diagnoses 0 1(5.6) The severity of baseline suicidal thoughts Beck Suicide Inventory 26.2(9.3) 18.7(8.1) Visual Analog Scale 7.5(1.8) 7.1(1.7) Treatment Effects Repeated measure analysis of variance ​​showed that the intensity of suicidal thoughts based on the Beck Scale for Suicidal Ideation(BSSI) and Visual Analogue Scale (VAS) decreased moderately in both of the intervention groups over time with a moderate to large effect size (Cohen’s f was 0.61 and 0.31 for the BSSI and the VAS respectively). However, the change in the severity of suicidal thoughts did not significantly differ between the ketamine and midazolam groups(Table 2 ). Table 2 Main treatment effects: BSSI: Beck scale for suicidal ideation, VAS: visual analog scale. Jacob Cohen has suggested that the values of 0.10, 0.25, and 0.40 represent small, medium, and large effect sizes for Cohen’s f, respectively. The effect of time Interaction of time and intervention group Outcome F p 2 η Cohen’s f power F p 2 η Cohen’s f power 21.10 <0.001 0.38 0.61 1 0.75 0.46 0.02 0.022 0.16 BSSI 11.27 <0.001 0.25 0.33 0.98 0.27 0.24 0.06 0.063 0.43 VAS Adverse events were sought and recorded in uniform notes at the outcome measurement time points. The most commonly reported side effect was mild nausea in the ketamine group. Discussion In this double-blind randomized controlled trial, we compared the efficacy of ketamine compared to the active comparison of midazolam in the instant amelioration of suicidal thoughts in patients with severe suicidal ideation. Although the severity of suicidal thoughts decreased in both study arms, we did not find a significant difference between groups. Contrary to our findings, a similar randomized clinical trial in 2017 with 80 adult participants with major depressive disorder and severe suicidal ideation reported that patients receiving ketamine experienced a larger reduction in Suicidal Ideation Scores (4.96 points) after 24 hours (95% CI = 2.33, 7.59; Cohen's d = 0.75)( 13 ). Our smaller sample size and the differences in study arms at baseline may explain the lack of a significant difference in our study. Moreover, a relatively large proportion of the patients receiving midazolam in our study had comorbid BPD in contrast to the 2017 trial wherein the opposite was true. Also, 54% of their patients were receiving antidepressants which may have interacted with the pharmacological effects of ketamine and midazolam ( 14 ). Another randomized double-blind trial compared ketamine with a placebo in 156 individuals across a spectrum of psychiatric diagnoses. They reported that two 40-minute IV doses of ketamine significantly reduced suicidal ideation on day three (to a score of lower than 3) (odds ratio 3.7 (95% CI 1.9 to 7.3), P < 0.001)( 15 ). The largest effects in their study were observed in patients with bipolar disorder and the results were not significant for the depression subgroup( 15 ). They proposed that the underlying diagnoses may affect the efficacy of ketamine in the reduction of suicidal thoughts( 15 ). Their study's large effect sizes may be due to their pharmacologically inactive comparison(placebo) or the nature of their participants’ diagnosis. The high rate(19/36 [52%] of BPD in our study participants and especially in the midazolam group(13/18(72%) was notable. Although there is no direct evidence that these individuals respond differently to ketamine or midazolam( 16 ), the common notion is that patients with BPD may experience spontaneous resolution of suicidal thoughts( 17 , 18 ). Thus, the effects of ketamine may have been underestimated in our study due to the higher rate of spontaneous resolution of suicidal thoughts in the comparison group. The effects of ketamine may vary based on the underlying diagnoses. Specifically, it is unclear how suicidal thoughts may respond to ketamine or other pharmacological agents among patients with borderline personality disorder. Since there is no evidence that individuals with borderline personality may respond differently to ketamine, the issue warrants further evaluation in larger and adequately powered trials. We suggest trials with larger sample sizes and stratification for borderline personality and other important diagnoses to facilitate subgroup analyses based on psychiatric comorbidities. Limitations This pilot trial had several limitations that should be considered when interpreting the results and in designing future trials. First, the small sample size as is usual for pilot trials likely prevented the detection of significant effects and limited the ability to conduct subgroup analyses and adjust for confounding factors. Secondly, the groups were not comparable at baseline in terms of depression severity and the rate of borderline personality disorder, despite randomization. This suggests the observed effects may not be solely due to the drugs. Thirdly, our study included patients with diverse psychiatric diagnoses, which increased practical relevance in the emergency setting but may have reduced statistical power due to the variability of ketamine efficacy across disorders. Conclusions The findings suggest that a single dose of ketamine may have a short-term effect on reducing the severity of suicidal ideation, consistent with previous studies. Declarations Ethics approval This study was approved by the IRB at Iran University of Medical Sciences (Ethics reference: IR.IUMS.FMD.REC.1399.069). Consent to participate All patients provided informed consent upon enrollment. Consent for publication All participants provided informed consent that their anonymous data be shared. Protocol Registration The protocol for this RCT was registered at the Iranian Registry of Clinical Trials (IRCT) and can be accessed at: https://www.fa.irct.ir/trial/61365. Availability of data and materials The data are available upon contact with the corresponding author. Competing interests The authors have no competing interests to declare. Funding We did not receive any funding for this study. Authors’ Contributions: M.B. K.A. AH.JN. contributed to the study design. M.B. conducted the main assessments and the data gathering. K.A. conducted the statistical analysis and supervised methodological aspects. K.M. and M.N.L. contributed to patient recruitment, medication administration, and data gathering. F.B. and MA.KA interpreted the data and prepared the tables and the manuscript. All authors reviewed the manuscript. Acknowledgments None References Kastrup MC. Health Coverage and Mental Illness: The Ongoing Issue of Mental Health Gap (mhGAP). Indian J Social Psychiatry. 2016;32(3):251–3. World Health O. mhGAP intervention guide for mental, neurological and substance use disorders in non-specialized health settings: mental health Gap Action Programme (mhGAP). version 2.0 ed. Geneva: World Health Organization; 2016 2016. Weber AN, Michail M, Thompson A, Fiedorowicz JG. Psychiatric emergencies: assessing and managing suicidal ideation. Med Clin. 2017;101(3):553–71. Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Adv Psychopharmacol. 2014;4(2):75–99. Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay MA, Baker GB, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Therapeutic Adv Psychopharmacol. 2020;10:2045125320916657. Ballard ED, Fields J, Farmer CA, Zarate CA Jr. Clinical trials for rapid changes in suicidal ideation: Lessons from ketamine. Suicide Life-Threatening Behav. 2021;51(1):27–35. Siegel AN, Di Vincenzo JD, Brietzke E, Gill H, Rodrigues NB, Lui LM, et al. Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review. J Psychiatr Res. 2021;137:426–36. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry. 2018;175(2):150–8. Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials. Australian New Z J Psychiatry. 2019;54(1):29–45. Ahmadpanah M, Sheikhbabaei M, Haghighi M, Roham F, Jahangard L, Akhondi A, et al. Validity and test-retest reliability of the Persian version of the Montgomery-Asberg Depression Rating Scale. Neuropsychiatr Dis Treat. 2016;12:603–7. Bagby RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton Depression Rating Scale: Has the Gold Standard Become a Lead Weight? Am J Psychiatry. 2004;161(12):2163–77. Esfahani M, Hashemi Y, Alavi K. Psychometric assessment of Beck scale for suicidal ideation (BSSI) in general population in Tehran. MJIRI. 2015;29(1):862–71. Abbar M, Demattei C, El-Hage W, Llorca P-M, Samalin L, Demaricourt P et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022;376. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. 2018;175(4):327–35. Domany Y, Shelton RC, McCullumsmith CB. Ketamine for acute suicidal ideation. An emergency department intervention: A randomized, double-blind, placebo‐controlled, proof‐of‐concept trial. Depress Anxiety. 2020;37(3):224–33. Chen KS, Dwivedi Y, Shelton RC. The effect of IV ketamine in patients with major depressive disorder and elevated features of borderline personality disorder. J Affect Disord. 2022;315:13–6. LINKS PS, Boggild A, Sarin N. Modeling the relationship between affective lability, impulsivity, and suicidal behavior in patients with borderline personality disorder. J Psychiatric Practice®. 2000;6(5):247–55. Rizk MM, Choo T-H, Galfalvy H, Biggs E, Brodsky BS, Oquendo MA, et al. Variability in suicidal ideation is associated with affective instability in suicide attempters with borderline personality disorder. Psychiatry. 2019;82(2):173–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 12 Feb, 2025 Read the published version in BMC Research Notes → Version 1 posted Editorial decision: Revision requested 30 Sep, 2024 Reviews received at journal 29 Sep, 2024 Reviewers agreed at journal 24 Sep, 2024 Reviewers agreed at journal 23 Sep, 2024 Reviewers agreed at journal 22 Sep, 2024 Reviews received at journal 18 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviews received at journal 09 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers agreed at journal 21 Jul, 2024 Reviewers invited by journal 21 Jul, 2024 Editor invited by journal 19 Jul, 2024 Editor assigned by journal 12 Jul, 2024 Submission checks completed at journal 12 Jul, 2024 First submitted to journal 10 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Lessons Learned from A Pilot Randomized Controlled Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eSuicide causes a total of about 700,000 annual deaths globally(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The World Health Organization (WHO) has identified suicide as a priority condition in the Mental Health Gap Action Programme (mhGAP) launched in 2008(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The mhGAP aims to scale up services for mental, neurological, and substance use disorders in low- and middle-income countries(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The WHO Mental Health Action Plan 2013\u0026ndash;2030 has set a global target of reducing the suicide rate in countries by one-third by 2030(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSuicidal ideation, especially when severe, is considered a medical emergency(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although antidepressants reduce suicidal ideation by controlling other symptoms of depression, their optimal clinical effects usually take weeks to months(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Ketamine at subanesthetic doses is the only FDA-approved antidepressant with its onset of action within a few hours(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Ketamine has also been investigated for its rapid effects on reducing suicidal thoughts independent of its antidepressant effect(\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNumerous studies have shown that the rapid antidepressant effect of ketamine in depression can reduce suicidal thoughts in patients with major depressive disorder with suicidal ideation(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, the efficacy may vary in different patients based on their diagnosis and further trials are needed to assess its safety and efficacy across psychiatric diagnoses and settings(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eWe aimed to compare the anti-suicidal effects of Ketamine infusion to Midazolam for rapid remediation of acute suicidal thoughts in patients admitted to the hospital with severe suicidal ideation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSetting, Participants, and Design\u003c/h2\u003e \u003cp\u003e This double-blind randomized controlled trial was approved by the ethics committee of Iran University of Medical Sciences (Ethics reference number: IR.IUMS.FMD.REC.1399.069) and registered in the Iranian Registry of Clinical Trials (IRCT20220118053756N1). It was conducted from January to July 2022 at two university hospitals in Tehran, Iran.\u003c/p\u003e \u003cp\u003ePatients aged 18\u0026ndash;65 with acute suicidal ideation associated with major depression were recruited. Written informed consent was obtained from patients and their legal guardians prior to enrollment. Acute suicidal thoughts were defined as thoughts starting within 72 hours before admission, associated with serious risk, and requiring psychiatric hospitalization. Thirty-six patients meeting the inclusion criteria were enrolled via convenience sampling and randomized to receive either a single-dose ketamine or midazolam infusion.\u003c/p\u003e \u003cp\u003eExclusion criteria included physical disorders (thyroid disorder, diabetes, hypertension, stroke, brain surgery, neurological disorders, seizures), allergy to ketamine or midazolam, pregnancy, and lactation. Patients taking antidepressants regularly in the previous month were also excluded.\u003c/p\u003e \u003cp\u003eThe effect was evaluated using the suicide visual analog scale (S-VAS) and Beck Suicide Severity Inventory (BSSI) at baseline, 12 hours (10\u0026ndash;14 hours), and 24 hours after administering the medication (22\u0026ndash;26 hours).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRandomization, Allocation Concealment, and Blinding\u003c/h2\u003e \u003cp\u003eOne researcher coded Ketamine and Midazolam as A and B. The second researcher who was unaware of the coding created a blocked random sequence of A and B using a computer-generated list of random numbers. The same researcher maintained the list. The recruiting researcher was unaware of the patient group at the time of assignment and would contact the second researcher to inquire the patient assignment.\u003c/p\u003e \u003cp\u003eMidazolam and Ketamine were prepared in packages with the same appearance and labeled as A and B. To prevent the sedative effects of Midazolam altering the masking, Midazolam was administered at a low non-sedative dose.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eThe patients received either a single dose of Ketamine hydrochloride (Exir Pharmaceutical Company, Iran) infusion 0.5 mg/kg or Midazolam(Daroo Pakhsh Co. Iran) 0.02 mg/kg infusion in 100 cc sodium chloride 0.9% over 40 minutes. The patient\u0026rsquo;s blood pressure, level of consciousness, and blood oxygen saturation, heart and breathing rate during the injection were monitored throughout the infusion. Either a physician or a highly skilled anesthetist was stand-by at the participant\u0026rsquo;s bedside throughout the infusion to handle emergency tracheal intubation or cardiopulmonary resuscitation if required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measurement\u003c/h2\u003e \u003cp\u003eA psychiatrist, who was blinded to the intervention, interviewed all participants before, 12 hours after, and 24 hours after administration of the medication, and filled Hamilton\u0026rsquo;s scale and BSSI. The same outcome assessor explained the protocol and administered the S-VAS to the participants. The main outcomes were suicidal ideation and the secondary outcome was the severity of depression.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eHamilton's scale:\u003c/h2\u003e \u003cp\u003eHamilton\u0026rsquo;s scale measures the severity of depression through 17 questions encompassing symptoms of depression including mood, guilt, sleep pattern, and suicidal thoughts. Scores above 22 point to very severe depression(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eBeck Scale for Suicidal Ideation:\u003c/h2\u003e \u003cp\u003eThe Beck scale for suicidal ideation (BSSI) consists of 19 items that assess suicidality in detail. The score obtained from BSSI ranges from 0 to 38; the higher the score, the more severe the suicidal thoughts (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The Persian version of this instrument has also been deemed valid and reliable(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eS-VAS (Suicide visual analog scale):\u003c/h2\u003e \u003cp\u003eThe Visual Analogue Scale, a method for measuring the severity of an experience subjectively, has been standardized and widely used for assessing suicidal ideation (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eThe obtained data were analyzed by SPSS-26 software. Repeated measures ​​analysis of variance (ANOVA) was used except for the change in VAS before treatment and 12 hours post-treatment in the midazolam group. In all cases, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 36 patients were randomized 1:1 to the study groups (Fig.\u0026nbsp;1). Other baseline characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Except for borderline personality disorder(BPD), there was no difference between the two groups. The severity of suicidal thoughts based on BSSI scores was higher in the midazolam group than in the ketamine group at the beginning of the study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTable of Baseline Characteristics of Trial Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipant Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCategories\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMidazolam\u003c/p\u003e \u003cp\u003eNumber(percent)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKetamine\u003c/p\u003e \u003cp\u003eNumber(percent)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(55.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13(72.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMarital Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(61.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10(55.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7(38.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDivorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccupational Status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEmployed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9(50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eEducation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBelow high school diploma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh school diploma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(44.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUniversity education\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9(50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ePersonal History\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdmission in psychiatric hospitals\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14(77.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSuicidal attempt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(44.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBorderline personality disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubstance use disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFamily history of\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMood disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13(72.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSuicidal attempt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(27.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCurrent Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMajor Depressive Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(44.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBipolar Disorder-I\u003c/p\u003e \u003cp\u003eDepressive Episode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBipolar Disorder-I\u003c/p\u003e \u003cp\u003eManic Episode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(22.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePersonality Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3(16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnxiety Disorders/ Obsessive Compulsive Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePsychiatric comorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMajor Depressive Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(5.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eObsessive Compulsive Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(11.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther Diagnoses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eThe severity of baseline suicidal thoughts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBeck Suicide Inventory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.2(9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.7(8.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVisual Analog Scale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5(1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.1(1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTreatment Effects\u003c/h2\u003e \u003cp\u003eRepeated measure analysis of variance ​​showed that the intensity of suicidal thoughts based on the Beck Scale for Suicidal Ideation(BSSI) and Visual Analogue Scale (VAS) decreased moderately in both of the intervention groups over time with a moderate to large effect size (Cohen\u0026rsquo;s f was 0.61 and 0.31 for the BSSI and the VAS respectively). However, the change in the severity of suicidal thoughts did not significantly differ between the ketamine and midazolam groups(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cem\u003eTable 2 Main treatment effects: BSSI: Beck scale for suicidal ideation, VAS: visual analog scale. Jacob Cohen has suggested that the values of 0.10, 0.25, and 0.40 represent small, medium, and large effect sizes for Cohen\u0026rsquo;s f, respectively.\u003c/em\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"44.89795918367347%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eThe effect of time\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.87755102040816%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eInteraction of time and intervention group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.224489795918368%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eOutcome\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.63855421686747%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eF\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003ep\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003csup\u003e\u003cspan dir=\"LTR\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003cspan dir=\"LTR\"\u003e\u0026eta;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eCohen\u0026rsquo;s f\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.843373493975903%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003epower\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eF\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003ep\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.63855421686747%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003csup\u003e\u003cspan dir=\"LTR\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003cspan dir=\"LTR\"\u003e\u0026eta;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eCohen\u0026rsquo;s f\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003epower\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.51063829787234%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e21.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.38\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.61\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.574468085106384%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.75\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.46\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.51063829787234%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.022\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.16\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.702127659574469%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eBSSI\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.51063829787234%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e11.27\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026lt;0.001\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.25\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.33\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.574468085106384%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.98\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.27\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.24\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.51063829787234%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.06\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.063\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.43\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.702127659574469%\" valign=\"top\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eVAS\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\u003c/br\u003e\u003cp\u003eAdverse events were sought and recorded in uniform notes at the outcome measurement time points. The most commonly reported side effect was mild nausea in the ketamine group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this double-blind randomized controlled trial, we compared the efficacy of ketamine compared to the active comparison of midazolam in the instant amelioration of suicidal thoughts in patients with severe suicidal ideation. Although the severity of suicidal thoughts decreased in both study arms, we did not find a significant difference between groups.\u003c/p\u003e \u003cp\u003eContrary to our findings, a similar randomized clinical trial in 2017 with 80 adult participants with major depressive disorder and severe suicidal ideation reported that patients receiving ketamine experienced a larger reduction in Suicidal Ideation Scores (4.96 points) after 24 hours (95% CI\u0026thinsp;=\u0026thinsp;2.33, 7.59; Cohen's d\u0026thinsp;=\u0026thinsp;0.75)(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Our smaller sample size and the differences in study arms at baseline may explain the lack of a significant difference in our study. Moreover, a relatively large proportion of the patients receiving midazolam in our study had comorbid BPD in contrast to the 2017 trial wherein the opposite was true. Also, 54% of their patients were receiving antidepressants which may have interacted with the pharmacological effects of ketamine and midazolam (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother randomized double-blind trial compared ketamine with a placebo in 156 individuals across a spectrum of psychiatric diagnoses. They reported that two 40-minute IV doses of ketamine significantly reduced suicidal ideation on day three (to a score of lower than 3) (odds ratio 3.7 (95% CI 1.9 to 7.3), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001)(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The largest effects in their study were observed in patients with bipolar disorder and the results were not significant for the depression subgroup(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). They proposed that the underlying diagnoses may affect the efficacy of ketamine in the reduction of suicidal thoughts(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Their study's large effect sizes may be due to their pharmacologically inactive comparison(placebo) or the nature of their participants\u0026rsquo; diagnosis. The high rate(19/36 [52%] of BPD in our study participants and especially in the midazolam group(13/18(72%) was notable. Although there is no direct evidence that these individuals respond differently to ketamine or midazolam(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), the common notion is that patients with BPD may experience spontaneous resolution of suicidal thoughts(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Thus, the effects of ketamine may have been underestimated in our study due to the higher rate of spontaneous resolution of suicidal thoughts in the comparison group.\u003c/p\u003e \u003cp\u003eThe effects of ketamine may vary based on the underlying diagnoses. Specifically, it is unclear how suicidal thoughts may respond to ketamine or other pharmacological agents among patients with borderline personality disorder. Since there is no evidence that individuals with borderline personality may respond differently to ketamine, the issue warrants further evaluation in larger and adequately powered trials. We suggest trials with larger sample sizes and stratification for borderline personality and other important diagnoses to facilitate subgroup analyses based on psychiatric comorbidities.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis pilot trial had several limitations that should be considered when interpreting the results and in designing future trials. First, the small sample size as is usual for pilot trials likely prevented the detection of significant effects and limited the ability to conduct subgroup analyses and adjust for confounding factors.\u003c/p\u003e \u003cp\u003eSecondly, the groups were not comparable at baseline in terms of depression severity and the rate of borderline personality disorder, despite randomization. This suggests the observed effects may not be solely due to the drugs.\u003c/p\u003e \u003cp\u003eThirdly, our study included patients with diverse psychiatric diagnoses, which increased practical relevance in the emergency setting but may have reduced statistical power due to the variability of ketamine efficacy across disorders.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe findings suggest that a single dose of ketamine may have a short-term effect on reducing the severity of suicidal ideation, consistent with previous studies.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eEthics approval\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the IRB at Iran University of Medical Sciences (Ethics reference: IR.IUMS.FMD.REC.1399.069).\u003c/p\u003e\n\u003ch2\u003eConsent to participate\u003c/h2\u003e\n\u003cp\u003eAll patients provided informed consent upon enrollment.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eAll participants provided informed consent that their anonymous data be shared.\u003c/p\u003e\n\u003ch2\u003eProtocol Registration \u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe protocol for this RCT was registered at the Iranian Registry of Clinical Trials (IRCT) and can be accessed at: https://www.fa.irct.ir/trial/61365. \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe data are available upon contact with the corresponding author.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors have no competing interests to declare.\u003c/p\u003e\n\u003ch2\u003eFunding\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eWe did not receive any funding for this study.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; Contributions:\u003c/h2\u003e\n\u003cp\u003eM.B. K.A. AH.JN. contributed to the study design. M.B. conducted the main assessments and the data gathering. K.A. conducted the statistical analysis and supervised methodological aspects. K.M. and M.N.L. contributed to patient recruitment, medication administration, and data gathering. F.B. and MA.KA interpreted the data and prepared the tables and the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKastrup MC. Health Coverage and Mental Illness: The Ongoing Issue of Mental Health Gap (mhGAP). Indian J Social Psychiatry. 2016;32(3):251\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health O. mhGAP intervention guide for mental, neurological and substance use disorders in non-specialized health settings: mental health Gap Action Programme (mhGAP). version 2.0 ed. Geneva: World Health Organization; 2016 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeber AN, Michail M, Thompson A, Fiedorowicz JG. Psychiatric emergencies: assessing and managing suicidal ideation. Med Clin. 2017;101(3):553\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaddy C, Giaroli G, White TP, Shergill SS, Tracy DK. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Adv Psychopharmacol. 2014;4(2):75\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatveychuk D, Thomas RK, Swainson J, Khullar A, MacKay MA, Baker GB, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Therapeutic Adv Psychopharmacol. 2020;10:2045125320916657.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBallard ED, Fields J, Farmer CA, Zarate CA Jr. Clinical trials for rapid changes in suicidal ideation: Lessons from ketamine. Suicide Life-Threatening Behav. 2021;51(1):27\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel AN, Di Vincenzo JD, Brietzke E, Gill H, Rodrigues NB, Lui LM, et al. Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review. J Psychiatr Res. 2021;137:426\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry. 2018;175(2):150\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials. Australian New Z J Psychiatry. 2019;54(1):29\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmadpanah M, Sheikhbabaei M, Haghighi M, Roham F, Jahangard L, Akhondi A, et al. Validity and test-retest reliability of the Persian version of the Montgomery-Asberg Depression Rating Scale. Neuropsychiatr Dis Treat. 2016;12:603\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagby RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton Depression Rating Scale: Has the Gold Standard Become a Lead Weight? Am J Psychiatry. 2004;161(12):2163\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEsfahani M, Hashemi Y, Alavi K. Psychometric assessment of Beck scale for suicidal ideation (BSSI) in general population in Tehran. MJIRI. 2015;29(1):862\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbbar M, Demattei C, El-Hage W, Llorca P-M, Samalin L, Demaricourt P et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022;376.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. 2018;175(4):327\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDomany Y, Shelton RC, McCullumsmith CB. Ketamine for acute suicidal ideation. An emergency department intervention: A randomized, double-blind, placebo‐controlled, proof‐of‐concept trial. Depress Anxiety. 2020;37(3):224\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen KS, Dwivedi Y, Shelton RC. The effect of IV ketamine in patients with major depressive disorder and elevated features of borderline personality disorder. J Affect Disord. 2022;315:13\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLINKS PS, Boggild A, Sarin N. Modeling the relationship between affective lability, impulsivity, and suicidal behavior in patients with borderline personality disorder. J Psychiatric Practice\u0026reg;. 2000;6(5):247\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRizk MM, Choo T-H, Galfalvy H, Biggs E, Brodsky BS, Oquendo MA, et al. Variability in suicidal ideation is associated with affective instability in suicide attempters with borderline personality disorder. Psychiatry. 2019;82(2):173\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Suicide, Ketamine, Midazolam, N-methyl-d-aspartate receptor antagonist, Depressive Disorder","lastPublishedDoi":"10.21203/rs.3.rs-4718815/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4718815/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eKetamine has emerged as a promising agent for the rapid reduction of suicidal thoughts. However, its efficacy across a broader spectrum of psychiatric disorders remains underexplored.\u003c/p\u003e\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate the efficacy of a single infusion of ketamine in inducing rapid remission of severe suicidal ideation, compared to Midazolam, in a population with acute suicidal thoughts.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn a double-blind randomized controlled trial conducted in Tehran, Iran, from January to July 2022 (IRCT20220118053756N1), 36 inpatients with acute severe suicidal ideation were enrolled. Participants were randomly assigned to receive either a single dose of ketamine (0.5 mg/kg) or Midazolam (0.02 mg/kg). Suicidality was assessed using the Beck Scale for Suicide Ideation (BSSI) and the Suicide-Visual Analog Scale (S-VAS) before the intervention and at 12 and 24 hours post-administration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAt baseline, the Midazolam group exhibited significantly higher BSSI scores and a higher rate of borderline personality disorder than the Ketamine group. Mean BSSI and S-VAS scores at 12 and 24 hours after the treatment in both groups. Despite these observations, no statistically significant differences were found between the groups in terms of BSSI and S-VAS scores.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe findings suggest that ketamine may reduce suicidal ideation, but its efficacy varies by psychiatric diagnosis. The groups were not significantly different in the main study outcomes.\u003c/p\u003e","manuscriptTitle":"Is Ketamine Efficacious for Rapid Treatment of Acute Suicidal Ideation in an Emergency Setting? 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