Your patient is a 58 y/o male with admitted as an inpatient in the Psychiatric unit for depression. He is doing well, until he suddenly has an acute attack where he is stating that he wants to kill himself. One of your coworkers was recently discussing using ketamine as a treatment to help reduce his suicidal ideation.

Question: As compared to placebo (midazolam/ saline), is ketamine an effective treatment for reducing acute suicidal ideation and suicidal behavior in patients with mood disorders?

PICO Question:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

P	I	C	O
Patients with acute suicidal ideation	Ketamine	Placebo control (saline solution)	Decrease in Suicidal ideation
Patients with depression	IV Ketamine	Midazolam	Decrease in suicidality
Patients with Bipolar Disorder	Intranasal ketamine	Placebo nasal spray	Decrease in suicidal behavior
Patients with suicidal ideations
Patients with mood disorders

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done.

1. Google Scholar–” Ketamine for suicidal ideation systematic review”- 11,800 results

1.  since 2017- 5,430 results- this was still a lot of results, so I skimmed the first few pages, looking specifically for articles that were systematic reviews/ meta-analyses, and articles that included a PDF on the side (since unfortunately I do not have access to the full PDF version of a lot of articles.) I mainly used this as a starting point to see in general what is out there about the topic, before I looked at more specific databases that would give me less of an overwhelming amount of results.
2. Pubmed-” ketamine for suicidal ideation”- 250 results
   1.  since 2017→ 203 results
   1. Filter: systematic review, meta-analysis- 16 results→ I thought 16 results was a good amount so I looked through all of these, and found quite a few that fit my search question
3. Science Direct– “ketamine for sucidial ideation”- 1,064 results
   1. Since 2017- 562 results
   1. Filter: Review articles- 159 results→ I looked through these and focused specifically on suicidal ideation, as opposed to depression 

These 3 search tools gave me sufficient articles that had high quality evidence and fit my PICO question well, so I did not look further at other databases

Articles Chosen (5 or more) for Inclusion (please copy and paste the abstract with link):

Please pay attention to whether the articles actually address your question and whether they are the highest level of evidence available.  If you cannot find high quality articles, be prepared to explain the extensiveness of your search and why there aren’t any better sources available.

Please note that if the evidence is not in the abstract, you must clearly summarize the evidence in your posting.

1. Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials

Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, Cipriani A, Hawton K. Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials. Aust N Z J Psychiatry. 2020 Jan;54(1):29-45. doi: 10.1177/0004867419883341. Epub 2019 Nov 15. Erratum in: Aust N Z J Psychiatry. 2020 Jul;54(7):766. PMID: 31729893.

Abstract

Objective: Ketamine may reduce suicidal ideation in treatment-resistant depression. But it is not known how quickly this occurs and how long it persists. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality.

Method: CENTRAL, EMBASE, Medline, and PsycINFO were searched until 12 December 2018. Randomised controlled trials of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included. Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Standardised mean difference was used for continuous outcomes.

Results: Twenty-five reports from 15 independent trials, with a total of 572 participants diagnosed with predominately affective disorders, were included. The evidence was rated moderate to low. In most trials, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. Only a single trial of intranasal esketamine was identified. At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardised mean difference = -0.51, 95% confidence interval = [-1.00, -0.03]), which persisted until 72 hours post-infusion (time points between 12 and 24 hours: standardised mean difference = -0.63, 95% confidence interval = [-0.99, -0.26]; between 24 and 72 hours: standardised mean difference = -0.57, 95% confidence interval = [-0.99, -0.14]), but not thereafter. However, there was marked heterogeneity of results. In a single trial of esketamine, marginal effects on suicidal ideation were observed. In terms of actual suicidal behaviour, there were virtually no data on effects of ketamine or esketamine.

Conclusion: A single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts. While confirmation of these results in further trials is needed, they suggest possible use of ketamine to treat acute suicidality. Means of sustaining any anti-suicidal effect need to be found.

• The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis

Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, Sos P, Wang G, Zarate CA Jr, Sanacora G. 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 Feb 1;175(2):150-158. doi: 10.1176/appi.ajp.2017.17040472. Epub 2017 Oct 3. PMID: 28969441; PMCID: PMC5794524.

Abstract

Objective: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.

Method: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration.

Results: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen’s d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine’s effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.

Conclusions: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine’s effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine’s long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

• The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis

Xiong J, Lipsitz O, Chen-Li D, Rosenblat JD, Rodrigues NB, Carvalho I, Lui LMW, Gill H, Narsi F, Mansur RB, Lee Y, McIntyre RS. The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. J Psychiatr Res. 2021 Feb;134:57-68. doi: 10.1016/j.jpsychires.2020.12.038. Epub 2020 Dec 11. PMID: 33360864.

Abstract

The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase, Medline, and PubMed from inception to July 1st, 2020. Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/routes at various time points were computed using random-effects models. With data from nine eligible RCTs (n = 197), the pooled effect size for anti-SI effects at the 24-h time point was 1.035 (N = 6, CI: 0.793 to 1.277, p < 0.001) for intravenous (IV) racemic ketamine and 1.309 (N = 1, CI: 0.857 to 1.761, p < 0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified. The findings suggest that single-dose IV ketamine/IN esketamine is associated with robust reductions in suicidal thoughts at 2-h, 4-h, and 24-h post-intervention. In addition, future studies on IM/oral/sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration.

•  Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review

Siegel AN, Di Vincenzo JD, Brietzke E, Gill H, Rodrigues NB, Lui LMW, Teopiz KM, Ng J, Ho R, McIntyre RS, Rosenblat JD. Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review. J Psychiatr Res. 2021 May;137:426-436. doi: 10.1016/j.jpsychires.2021.03.009. Epub 2021 Mar 16. PMID: 33774537.

Abstract

Suicide accounts for approximately 800,000 deaths per year globally. Previous research has shown that intranasal esketamine and intravenous ketamine can rapidly decrease the severity of depressive symptoms and suicidal ideation. However, the majority of clinical trials excluded individuals with moderate to high baseline suicidality scores (e.g., suicidal ideation with plan/intent at the time of recruitment). The current review aims to evaluate the effect of esketamine and ketamine in patients with suicidal ideation at baseline. A systematic search was conducted on EMBASE, PsychInfo and PubMed from inception to July 2020 following the PRISMA guidelines. 15 studies met inclusion criteria. Results from esketamine trials did not demonstrate antisuicidal effects, as between-group differences were not found. Intravenous ketamine appeared to rapidly decrease the severity of suicidal ideation and depressive symptoms in individuals with baseline suicidal ideation, though retrospective studies suggest that these effects may be short-lasting. During the double-blind treatment phases, 2.4% of patients from the treatment groups and 1.5% of patients from control groups attempted suicide, with zero deaths by suicide in both the treatment and control groups during this phase. Based on the overall pooled samples, studies were assessed to be relatively safe, and the continual inclusion of this study population in future clinical trials is encouraged. Future research should aim to assess the longitudinal efficacy of ketamine in patients with baseline suicidality.

5)   Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial

 

Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, Marver JE, Burke AK, Milak MS, Sublette ME, Oquendo MA, Mann JJ. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. 2018 Apr 1;175(4):327-335. doi: 10.1176/appi.ajp.2017.17060647. Epub 2017 Dec 5. PMID: 29202655; PMCID: PMC5880701.

Abstract

Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.

Method: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).

Results: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen’s d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.

Conclusions: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.

For the Final Mini-CAT (Rotation 6) – YOU WILL COPY THE PARTS ABOVE AND COMPLETE THE REMAINING PARTS BELOW:

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
1) Witt K, Potts J, Hubers A, Grunebaum MF, Murrough JW, Loo C, Cipriani A, Hawton K (Jan, 2020)	Systematic Review/ Meta-analysis	15 RCTS with 572 adult participants aged between 15-80- most studies looked at those with unipolar depression, followed by bipolar depression, and one with anxiety disorders	Short and long term effectiveness of ketamine for suicidal ideation and suicidality	In most trials, ketamine was administered as .5 mg/kg, mostly on it’s own and along with ECT in 2 trials, usually IV but in a few studies also SC or IMKetamine was associated with a significant reduction in suicidal ideation scores within 4 hoursEffects in favor of ketamine between 4 hours→ 72 hours, though considerable heterogeneityNo significant treatment effect of ketamine for suicidal ideation between 72 hrs→ 2 weeksResults suggest that ketamine can be used for acute treatment of suicidal thoughtsAfter controlling for improvement in severity of depressive symptoms, ketamine’s effect on suicidal ideation remained significant, suggesting that ketamine has a specific effect on suicidal ideation independent of severity of depressive symptoms Controls were either saline or midazolam- when only midazolam were used, effects were more modest than when saline was usedOne study looked at self-harm behavior, attempted suicide and suicide, and no participant in either the ketamine or control group experienced any of these symptoms by follow up	– main limitation- limited info available from studies- the assessment of suicidal ideation mainly relied on a single item on a depression rating scale, and the scale varied between different studies – only one study investigated effects on suicidal behavior/ suicide attempts/ suicide, and no issues in either group, probably due to limited statistical power – unclear association between overt expression of suicidal ideation and risk of suicide-many patients who have died by suicide did not admit to suicidal ideas before their deaths – choice of control drug- placebo or midazolam(sedative)-neither are effective in treatment of depression or suicidality, so results might have been different if ketamine was compared to antidepressants – ethical considerations about off-label use of ketamine could have influenced which participants joined, and potential issue of rebound suicidality has not been investigated enough – trials did not report adverse effects beyond a few hours after treatment, even when ketamine was given in high doses – sample sizes in the trials were relatively small- 8 studies included less than 30 patients, so uncertainty about estimated effects
2) Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, Sos P, Wang G, Zarate CA Jr, Sanacora G. (October 2017)	Systematic Review/ Meta-analysis	Included 10 studies with 167 participants who met the criteria for baseline suicidal ideation. Participants either had major depression, bipolar  disorder, or PTSD.	Effectiveness of single dose of ketamine for suicidal ideation	Based on clinician-administered rating scales, ketamine reduced suicidal ideation more rapidly than with control treatments- significant benefits as early as 1 day after treatment and extending as long as 7 days after treatmentEffect sizes for ketamine on change in suicidal ideation were moderate- large at all time pointsKetamine was associated with significantly greater proportion of patients being free from suicidal ideation compared to control treatments at post-infusion days 1,2,3, and 7- over half of patients reported no suicidal ideation at all time pointsKetamine also significantly reduced suicidal ideation during all time points by self-report outcome measures, also with moderate-large effect sizesAmong patients who achieved resolution of suicidal ideation by 24 hours after infusion, effect of ketamine persisted for up to 1 week in 86% of patients compared to 52.9% who got control (self-reported- 89.2% vs 42.9%)	– limitations included very small sample sizes, limiting the sensitivity analysis of individual scales – all studies included only studied effect of ketamine on suicidal ideation, but unknown whether this translates to effects on suicidal behavior – although everyone included has baseline suicidal ideation, other than one study, they did not specifically recruit patients deemed at imminent risk of suicide. – short follow up of the studies- so cannot give any guidance on sustained effects of ketamine beyond 7 days after treatment – since ketamine has psychoactive properties, functionally, the trials using saline as the comparator are unblinding
3) Xiong J, Lipsitz O, Chen-Li D, Rosenblat JD, Rodrigues NB, Carvalho I, Lui LMW, Gill H, Narsi F, Mansur RB, Lee Y, McIntyre RS (February 2021)	Systematic Review/ Meta-analysis	9 RCT’s including 371 participants diagnosed with mood disorders, plus an additional 5 studies for qualitative analysis, that only included data on depression not SI	Acute anti-suicide effects of single-dose ketamine in different forms of administration	Looked at use of IV racemic ketamine in 8 studies, and 1 with intranasal ketamineNotable reductions in multiple item suicidal ideation scores were observed at 2 hours, 230 minutes, 4 hours, and 24 hours, in all but one study- which noted small but insignificant changesIV racemic ketamine had larger effect size at 230 min/4 hrs post-infusion and smaller effect size at 24 hours than IN esketamineUnable to identify RCT’s including oral/ sublingual/ IM forms of ketamine	– moderate heterogeneity between studies in terms of SI scale used, baseline SI, use of different controls, and presence of standard-of-care treatment/ hospitalization – several studies had extremely small sample sizesà this also led to inability to conduct tests for funnel plot asymmetry, so there could have been publication bias – severe SI in some patients may have rendered a greater dose of ketamine than what was given – implementation of psychiatric measures like hospitalization could have contributed to decreased suicidality, reducing the sensitivity of direct effects of ketamine – ability to reduce SI does not necessarily mean it reduces suicidal behavior
4) Siegel AN, Di Vincenzo JD, Brietzke E, Gill H, Rodrigues NB, Lui LMW, Teopiz KM, Ng J, Ho R, McIntyre RS, Rosenblat JD (May 2021)	Systematic Review	15 studies in total with 480 participants- 3 RCT’s assessing use of IN esketamine (total 263 patients), 5 RCT’s assessing use of IV ketamine (total 88 patients), 4 retrospective, open label trials (total 126 partipants), and 3 case studies,	Effect of ketamine and esketamine in patients with suicidal ideation at baseline	3 RCTs including 226 patients with active suicidality assessed effectiveness of intranasal esketamine→ in these studies MADRS (depression scale scores) reduced significantly more in esketamine treatment group than placebo nasal spray within 24 hours, however, improvements in suicidal ideation at the 24 hour mark, while occurring in both groups, did NOT improve more significantly in the esketamine treatment group than placebo, suggesting that IN eskematine is not effective in significantly reducing suicidal ideations5 RCTs assessed effect of subanasthetic IV ketamine compared to midazolam- at 24 hours after infusion, IV ketamine was significantly more effective at reducing suicidal ideation than midazolam→ treatment effects were usually maintained through 6 week clinical follow up Studies with repeat doses of ketamine (.5 mg twice weekly for 3 weeks) did not find a significant difference in suicidal ideation between this group and placebo7 retrospective studies found reductions in suicidal ideation within 24 hours, but the majority of patients did not have sustained effects post-treatment.Patients from all studies experienced mild adverse effects related to ketamine/ esketamine treatment (headaches, nausea, mild dissociation)During the double-blind phases of treatment, 2.4% of patients from the treatment groups and 1.5% of patients from control groups attempted suicide, with zero deaths by suicide in either groupThere were some serious adverse events related to suicide and depression in a few of the studies, but researchers deemed these to be unrelated to study participation.	– admitting patients at high-risk for suicide is a big intervention in and of itself, potentially explaining the high placebo response rates – biggest limitation is small sample size in both prospective and retrospective studies- this in combination with placebo effect could explain the lack of significant differences between groups -lack of longitudinal effects in RCT’s- difficult to understand longer term antisuicidal effects – concurrent psychotherapy is usually not mentioned in these pharmacological studies- psychotherapeutic interventions may help the initial response to ketamine as well as maintaining the effects longer term
5)Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, Marver JE, Burke AK, Milak MS, Sublette ME, Oquendo MA, Mann JJ.(April 2018)	Randomized Controlled Trial	RCT including 80 patients aged 18-65 years old with a diagnosis of Major Depressive disorder, score >/=16 on 17 item Hamilton Depression Score, and score of >/=4 on SSI, which is considered clinically significant for suicidal ideation	Effects of ketamine compared to midazolam (control) on suicidal ideation after 24 hours	Average SSI score at day 1 after treatment was 4.96 points lower in the ketamine group than in the midazolam groupDecrease in suicidal ideation at 230 minutes after the infusion was greater in the ketamine group than in the midazolam groupAmong those who continued to have suicidal ideation on day 1, greater improvement in ketamine group on suicidal ideation and desire subscaleOdds of SSI score of 0 on day 1 were 2.8 fold greater in ketamine group, but slightly short of being statistically significantWorsening of SSI ratings at 230 minutes were observed in 4 patients in the midazolam group, and at 1 day in 9 patients in midazolam group and 2 in ketamine groupImprovement in SI largely maintained at 6 week follow upParticipants in midazolam group reported higher anxiety after 230 minutes than ketamine group, but not significantNo reports of ketamine abuse at follow up at 3 and 6 monthsAE’s-mainly BP and dissociative symptoms- mild to moderate and typically resolved within minutes-hours after infusion10 serious AE-including 4 for suicide attempts and 3 for increased suicidal ideation within the study	-primary outcome measure was suicidal ideation, not suicidal behavior – among patients with baseline suicidal ideation, no effect of ketamine on suicidal planning subscale, but greater effect of ketamine on suicidal desire and ideation subscale – more patients with borderline personality disorders in ketamine group than midazolam group – open-label treatment during week 1-6 follow up, during which standard pharmacological treatments were optimized – small % of Hispanic and non-white participants (so lack of diversity)

Conclusion(s):
– Briefly summarize the conclusions of each article, then provide an overarching conclusion.

Summary of Conclusions:

1) In those with mood disorders, ketamine is effective in reducing suicidal ideation between 4 hours- 72 hours and can be used in short term treatment of suicidal ideation.

2) In those with baseline suicidal ideation, ketamine is effective in reducing suicidal ideation within 1 day and extending to 1 week after administration. Ketamine was found to be effective at reducing suicidal ideation both more rapidly and more effectively than control treatment.

3) In those with mood disorders, both IV ketamine and IN esketamine are effective at reducing suicidal ideation between 2 hours-24 hours after administration.

4) In patients with baseline suicidal ideation, IV ketamine, but not IM esketamine, is effective in acutely reducing suicidal ideation short term (24 hours).

5) In patients with depression and baseline suicidal ideation, IV ketamine was associated with a clinically significant reduction in suicidal ideation at day 1 as compared to midazolam, and improvement appeared to persist for at least 6 weeks (length of follow up.)

Overall Conclusion: IV Ketamine is effective at acutely reducing suicidal ideation in patients with mood disorders and baseline suicidal ideation, as early as 2 hours after infusion and extending up to even a few weeks after administration. There is limited evidence on effects of ketamine on suicidal behavior and attempt, so no conclusion can be made at this time about effects on suicidality. There is also limited evidence on effects of intranasal esketamine on suicidal ideation, but based on the evidence, it is not more effective than placebo at reducing suicidal ideation.

Clinical Bottom Line:

Please include an assessment of the following:

– Weight of the evidence – summarize the weaknesses/strengths of the articles and explain how they factored into your clinical bottom line (this may recap what you discussed in the criteria for choosing the articles)

– Magnitude of any effects

– Clinical significance (not just statistical significance)

– Any other considerations important in weighing this evidence to guide practice- If the evidence you retrieved was not enough to conclude an answer to the question, discuss what aspects still need to be explored and what the next studies will have to answer/provide (e.g. larger number, higher level of evidence, answer which sub-group benefits, etc)

Weight of the Evidence: 4 of my studies were systematic reviews and meta-analyses, so overall, they had the highest level of evidence possible, but the sample sizes of each were not very large, weakening the weight of the evidence. My fifth study was an RCT, which is still a high level of evidence, however it also had a fairly small sample size.

1)This study included 15 different articles with 572 patients in total, which is a moderate population size. However, each individual study did not include so much patients, with 8 studies including less than 30 patients. Thus, even though it is a systematic review/ meta-analysis, which is a very high level of evidence, the weight of the evidence as a whole is pretty low, because many of the studies used may not have reliable results due to their small sample sizes. Furthermore, the results had considerable heterogeneity, further weakening their weight. Some other weaknesses were mentioned in the limitations column, including the limited ways of assessing for suicidal ideation, limited data on actual suicidal behaviors, the choice of control drugs, and the lack of information about adverse effects related to ketamine, especially longer term. Some strengths of this article were that it was specifically dealing with patients with mood disorders, namely depression, which is specific to my question. But, it also was able to control for the mood disorders and find that ketamine was still able to independently reduce suicidal ideation when mood was controlled for, strengthening the claim that ketamine is effective specifically in reducing suicidal ideation. Another strength is that ketamine was compared to 2 different controls throughout the study- saline and midazolam- and the effects were more modest with midazolam, so there was able to be some comparison within controls as well. Finally, a strength is that at least one study included did look at suicidal behaviors, which is generally very limited in the research of ketamine.

2) This paper included 10 studies with 167 participants in total, which is a pretty small population size, especially for a systematic review and meta-analysis. Most of the studies included in the paper had very small sample sizes, causing the evidence received from the articles to carry less weight. Other weaknesses include that it did not study actual suicidal behaviors, only self-reported suicidal ideation, and did not have a long enough follow up period to assess for longer term effects of ketamine. This study also did not look at and consider possible adverse effects of ketamine. Some strengths of this paper are that it did follow up on patients for up to 1 week and see results for that time. It also looked at both clinician reported AND patient- reported suicidal ideation scales, and noted that ketamine reduced suicidal ideation on both scales, with large effect sizes. It also focused specifically on patients with baseline suicidal ideation, which is important since these are the patients who are at greatest risk of actually committing suicide. In addition, we can better evaluate the effects of ketamine if we know that all patients included really had suicidal ideation to begin with.

3) This study included 9 RCT’s with a total of 372 patients. It was a systematic review and meta-analysis, which is the highest level of evidence, but some of the studies had very small sample sizes, decreasing the weight of the evidence. Some other weaknesses were that, similar to other studies, it only looked at suicidal ideation, which does not necessarily predict suicidal behavior, there was moderate heterogeneity between the studies, and in some cases other factors could have contributed to the decrease in SI. Some strengths of this article are that it looked at both IV ketamine and intransala esketamine, though the sample size of the study with intranasal ketamine was small so there is porbably not enough evidence to make any statement about intranasal esketamine based on this paper. Other strengths are One strength that it included many RCT’s (7/9) that utilized multiple-item suicidal ideation scales, which assess suicidal ideation concerning several aspects, including ideation, planning, frequency and duration, etc, which is better than the scales used in some studies which only had one point about suicidal ideation. Furthermore, these scales have already been found to be correlated with suicidality, suggesting clinical predictive ability of using this to detect suicidality. Finally, a strength of this article is that it assesses effects of ketamine as soon as 2 hours after administration, showing the potential of very rapid and acute effects of ketamine.

4) This was a systematic review which included 3 RCT’s assessing use of IN esketamine (total 263 patients), 5 RCT’s assessing use of IV ketamine (total 88 patients), 4 retrospective, open label trials (total 126 participants), and 3 case studies, with 480 individuals total. Although the study did include a relatively large sample size, and especially for the 3 RCT’s assessing esketamine, the sample sizes of each study were larger, the rest of the studies including pretty small sample sizes individually, and there were 3 case studies, which weakens the strength of the evidence from individual studies. Other weaknesses are that there could have been a placebo effect due to emergent treatment in other ways (ie: hospitalization) of those with SI, and the lack of long term follow up toadequately assess possible long term effects of ketamine on SI. Some strengths of this study were that they looked at both IN esketamine and IV ketamine, and were able to find 3 studies with a significant sample size assessing the effects of IN esketamine, giving greater weight to the evidence regarding IN esketamine. It also discussed effects of repeated doses of ketamine, concluding that repeated doses did not achieve any effects. Other strengths are that it reported adverse effects related to ketamine, concluding that they were not significant nor concerning, and it discussed not only effects on suicidal ideation, but also discussed suicidal behavior, interestingly noting that suicide attempts were greater in the ketamine group than in the control group.

5) This is an RCT, which is a high level of evidence but not the highest level of evidence, and it includes 80 patients, which is a relatively small sample size. Thus, the weight of the evidence is not so strong and probably less than the other included studies. Furthermore, the primary outcome was suicidal ideation as opposed to suicidal behavior, and results may not necessarily be translatable. Some strengths are that it reports adverse effects, emphasizing that there were no significant adverse effects particular to one group and the AE of ketamine were short-lived post-infusion. Another strength is that it followed the patients for 6 weeks post-infusion and observed continued effects of ketamine in reducing SI.

Magnitude of Effects: Although 4/5 of the studies mentioned were systematic reviews/ meta-analyses, since none of the individual studies included such large sample sizes, the magnitude of effects remains quite small, especially for the intranasal esketamine (third study stated that it is and fourth study stated that it is not), but even for the IV ketamine, which was proven to be effective at reducing suicidal ideation in multiple studies. Also, in terms of timing, some studies looked at more acute effects, in as little as 2 hours after treatment, while other studies looked a little bit longer term, such as one week or up to 6 weeks, and the longer term results were mixed between the studies. In some studies the results were statistically significant, while in others they were not, but overall, it is hard to tell since results could be skewed (prove statistically insignificant when they really are significant or vice versa) with such small sample sizes.

Clinical Significance: I believe that these results are clinically significant, since according to all of the studies, whether statistically significant or not, ketamine was more effective than placebo and midazolam at reducing suicidal ideation. Despite the challenges and limited sample sizes, ketamine, especially the IV formulation but also the IN formulation, was consistently effective at reducing suicidal ideation, and although not all studies looked at adverse effects, those that mentioned them did not find any significant adverse effects associated with ketamine. There are very limited results related to actual suicidal behavior and attempt, though some of the scales used for suicidal ideation did ask questions related to attempt, such as asking about a plan. However, this research is not significant in posing that ketamine is effective in reducing suicidal behavior and activity. Nevertheless, overall, based on this research, I would be inclined to prescribe IV ketamine to my patient with current suicidal ideations in order to acutely treat his SI.

Other Considerations: The main consideration to keep in mind is the fact that suicidal ideation does not necessarily correlate with and predict suicidal behavior. Very few of the studies I found looked at suicidal behavior and attempt, and the ones that did were not able to adequately assess it. It is unfortunately quite difficult to look at actual suicide or attempts, since they have low base rates, even in at risk populations, so very large sample and long follow up periods would be required. Future studies should look at both the correlation between suicidal ideation and suicidal behavior/attempt, as well as the effects of ketamine more directly on suicidal behavior. Another consideration is that adverse effects and the ethical issue of using ketamine were not really addressed, or only slightly addressed, in these studies. I think that should be something that is emphasized more, since the main reason for not using ketamine would be due to these issues. If there were no adverse effects or harms associated with using ketamine, then even a small benefit on suicidal ideation would be worthwhile and beneficial to use. Future studies could also follow up longer after ketamine use to assess the long term effects of ketamine use on both suicidal ideation and suicidality, as well as potential longer term adverse effects. Finally, though some studies did attempt to look at different formulations of ketamine, there was limited evidence on IN esketamine, and no evidence that I found on other forms, such as IM ketamine, so future studies could look at different formulations. The use of ketamine for suicidal ideation is still a new innovation, so there is much yet to study, but based on my research, and especially because no medication has proven beneficial thus far, this does sound promising.