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Efficacy of Ketamine in the Treatment of Substance Use Disorders a Systematic Review

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Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial

BMJ 2022; 376 doi: https://doi.org/10.1136/bmj-2021-067194 (Published 02 Feb 2022) Cite this as: BMJ 2022;376:e067194

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Ketamine for suicidal ideation

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  1. Mocrane Abbar , chief of clinical department1,
  2. Christophe Demattei , statistician2,
  3. Wissam El-Hage , chief of clinical section3,
  4. Pierre-Michel Llorca , chief of clinical department4,
  5. Ludovic Samalin , assistant professor of psychiatry4,
  6. Pierre Demaricourt , chief of clinical department5,
  7. Raphael Gaillard , primary of clinical section5,
  8. Philippe Courtet , chief of clinical section6 7,
  9. Guillaume Vaiva , professor of psychiatry8 ix,
  10. Philip Gorwood , master of clinical departmentfive,
  11. Pascale Fabbro , methodologist2,
  12. Fabrice Jollant , professor of psychiatry1 v 10 11 12
  1. 1Department of Psychiatry, Academic Hospital (CHU) Nîmes, University of Montpellier, Nîmes, France
  2. 2Department of Biostatistics, Epidemiology, Public Wellness and Innovation in Methodology, CHU Nîmes, University of Montpellier, Nîmes, France
  3. 3CHRU Tours, Inquiry Unit of measurement (UMR) 1253, iBrain, Academy of Tours, National Institute for Health and Medical Enquiry (INSERM), Tours, French republic
  4. 4Department of Psychiatry, CHU Clermont-Ferrand, University of Clermont Auvergne, UMR 6602, Constitute Pascal, Clermont-Ferrand, France
  5. fiveSchoolhouse of Medicine, University of Paris and Sainte-Anne Hospital, Paris, France
  6. half-dozenINSERM, Centre for Epidemiological and Clinical Inquiry in Psychiatry (PSNREC), University of Montpellier, CHU Montpellier, Montpellier, France
  7. 7Department of Emergency Psychiatry and Astute Care, Lapeyronie Hospital, CHU Montpellier, Montpellier, France
  8. eightDepartment of Psychiatry, CHU Lille, Lille, French republic
  9. 9University of Lille, INSERM U1172 - LilNCog - Lille Neuroscience and Cognition, Lille, France
  10. tenDepartment of Psychiatry, McGill University, McGill Group for Suicide Studies, Montreal, QC, Canada
  11. 11Moods Team, INSERM, UMR-1178, Epidemiology and Population Health Research Centre (CESP), Le Kremlin-Bicêtre, France
  12. 12Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena, Germany
  1. Correspondence to: F Jollant jollantf{at}gmail.com
  • Accepted 3 December 2021

Abstruse

Objective To ostend the rapid onset anti-suicidal benefits of ketamine in the brusque term and at six weeks, overall and co-ordinate to diagnostic group.

Design Prospective, double blind, superiority, randomised placebo controlled trial.

Setting Seven French teaching hospitals betwixt 13 April 2015 and 12 March 2019.

Eligibility criteria for participants Aged 18 or older with electric current suicidal ideation, admitted to hospital voluntarily. Exclusion criteria included a history of schizophrenia or other psychotic disorders, substance dependence, and contraindications for ketamine.

Participants 156 participants were recruited and randomised to placebo (northward=83) or ketamine (n=73), stratified by centre and diagnosis: bipolar, depressive, or other disorders.

Intervention Ii xl minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) were administered at baseline and 24 hours, in add-on to usual treatment.

Primary event measures The primary outcome was the rate of patients in full suicidal remission at solar day 3, according to the scale for suicidal ideation total score ≤3. Analyses were conducted on an intention-to-care for basis.

Results More participants receiving ketamine reached full remission of suicidal ideas at day iii than those receiving placebo: 46 (63.0%) of 83 participants in the ketamine arm and 25 (31.6%) of 73 in the placebo arm (odds ratio 3.vii (95% confidence interval i.ix to vii.3), P<0.001). This issue differed according to the diagnosis (treatment: P<0.001; interaction: P=0.02): bipolar (odds ratio 14.1 (95% confidence interval 3.0 to 92.ii), P<0.001), depressive (1.3 (0.3 to 5.2), P=0.vi), or other disorders (three.vii (0.nine to 17.3, P=0.07)). Side effects were limited. No manic or psychotic symptom was seen. Moreover, a mediating effect of mental pain was plant. At week 6, remission in the ketamine arm remained loftier, although non-significantly versus placebo (69.five% v 56.3%; odds ratio 0.viii (95% conviction interval 0.iii to 2.5), P=0.7).

Conclusions The findings indicate that ketamine is rapid, safety in the brusk term, and has persistent benefits for acute care in suicidal patients. Comorbid mental disorders appear to be important moderators. An analgesic effect on mental pain might explain the anti-suicidal effects of ketamine.

Trial registration ClinicalTrials.gov NCT02299440.

Figure1

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Introduction

Around 700 000 people worldwide die from suicide annually, and 10 to 20 times this number attempt suicide.one Suicide is the second nearly important crusade of death in adolescents and young adults.2 The 12 month prevalence of suicidal ideas is 2% in the adult population globally, including 0.five% with a suicidal plan.3 Although most suicidal ideas will not lead to a suicidal act, all suicidal acts are preceded by suicidal ideas. Thus rapid resolution of a suicidal crisis earlier it is acted on might foreclose many deaths. Moreover, reducing the intensity of the suicidal pain could facilitate psychosocial intervention.

Only express testify based options are available to care for suicidal crises. Antidepressants might reduce the risk of suicide, specially in individuals anile over 25, but onset of beneficial furnishings is delayed by several weeks and a trial of several drugs is often necessary.4 Moreover, antidepressants are not recommended for people with bipolar disorders. Similarly, clozapine and lithium might be effective anti-suicidal drugs in schizophrenia and mood disorders, respectively, simply not in the short term.5 Psychotherapy takes several sessions to be efficient,6 and the testify for electroconvulsive therapy remains weak.5 Access to hospital, anxiolytics, and hypnotics are commonly used despite limited scientific evidence. Moreover, suicide occurs at high rates in psychiatric units during admission and after discharge, questioning the efficacy of this process.seven

Recently, ketamine has been shown to take a rapid effect on depressive symptoms and suicidal ideation afterwards a single dose.891011 A meta-analysis12 showed a beneficial issue on suicidal ideation scores inside 4 hours afterward infusion, lasting for at least the showtime 72 hours. Of note, a recent review of the literature suggested that intravenous ketamine has a ameliorate effect than intranasal esketamine.13 Previous studies, withal, were subject to several methodological limitations. Firstly, the suicidal risk was often poorly measured (eg, with 1 single item of a low calibration). Secondly, response (unremarkably defined as a 50% score reduction on a calibration) was the most common consequence rather than remission (that is, complete absence of suicidal ideas). Thirdly, samples were ordinarily small. Fourthly, nearly studies were conducted in unipolar disorder with limited cognition about the effect in bipolar disorder, despite the high suicide risk,14 and in non-mood disorders. Finally, the psychophysiological mechanisms of activity remain poorly understood. Notably, it is now established that mental pain contributes to an increased adventure of suicidal ideas and acts,15 suggesting that suicidal acts aim to put an finish to unbearable mental pain. Whether the antalgic furnishings of ketamine contribute to its anti-suicidal effects remains to be tested.

Nosotros aimed in this study to examine full remission of suicidal ideas 72 hours after ii infusions of ketamine versus placebo in a large sample. Three groups of patients were a priori selected: those with a bipolar disorder, or a depressive disorder, or another master diagnosis. Furthermore, we tested whether ketamine acted on suicidal ideas through an analgesic effect on mental hurting. Finally, we examined the persistence of the effect of ketamine at six weeks. We hypothesised that (a) ketamine volition exist better than placebo for inducing full suicidal remission at day iii; (b) this result will vary according to the diagnostic group; (c) this upshot will be mediated through alleviating mental pain; (d) this effect will persist over six weeks.

Methods

Study pattern

This six week, double blind, randomised placebo controlled report (named KETIS) was conducted in vii academic hospitals in metropolitan French republic. Ethical approving was obtained on 18 July 2014 from the research ethics board "Comité de Protection des Personnes (CPP) Sud Méditerranée III" (ref: 2014.06.03 bis). This report was prospectively registered on xx November 2014 on https://www.clinicaltrials.gov/ (NCT02299440), and is listed on EudraCT: 2014-001324-xxx. All patients gave their informed, written, and signed consent before inclusion.

Patients

Participants were recruited during admission to hospital in psychiatry for suicidal ideation. Inclusion criteria were patients aged 18 or older, with a clinician rated calibration for suicidal ideation (SSI16) total score >3; voluntarily admitted to hospital; French speaking; able to provide informed consent; insured or beneficiary of a health insurance programme. Exclusion criteria were a history of schizophrenia or other psychotic disorders based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-Four) criteria; schizoid or schizotypic personality disorders; presence of psychotic symptoms at initial interview; substance dependence during the preceding calendar month (except nicotine or caffeine); positive urine screening for illicit substances (except cannabis); pregnancy (known or positive at baseline urine test) or breastfeeding; unstable somatic status; known or suspected contraindication for ketamine, including hypersensitivity to ketamine, hypertension, course IV cardiac insufficiency, history of stroke, hepatic or cutaneous porphyria, history of intracranial hypertension; clinically important anomalies found during clinical test, biological tests or electrocardiogram; non-stabilised hypertension or hypertension >180/100; concomitant electroconvulsive therapy; electric current participation or participation within the past three months in another interventional study; patients under judicial protection or guardianship.

Randomisation and masking

Patients were randomised one:1 to placebo or ketamine afterwards inclusion, earlier perfusion training. Patients were further randomised by blocks of random size stratified by eye and by diagnostic category based on the Mini-International Neuropsychiatric Interview (MINI) five.0,17 using a programme adult specifically for the written report (SAS; Cary, NC). Participants were assigned a unique identification code. The three diagnostic categories were bipolar disorder; major depressive disorder; and any psychiatric disorder with no mention of a bipolar disorder, major depressive disorder, or any exclusion diagnosis (notably psychotic disorders and substance dependence; see exclusion criteria in "Patients" section).

Investigators and patients were blinded to study arm. The perfusion product was prepared within each participating section past a designated nurse, who was the only person with cognition of randomisation results. This nurse did not participate in other aspects of the report and kept the arm assignments secret. Both ketamine and placebo perfusions were transparent and visually similar.

Procedures

At baseline, a sociodemographic and clinical assessment was conducted comprising the MINI 5.017 for psychiatric diagnoses according to DSM-IV criteria; the SSI (both clinician rated and cocky-rated versions18); the clinician rated Columbia suicide severity rating scale (CSSRS)nineteen; the self-rated concrete and psychological pain-visual analogue calibration (PPP-VAS)20; the self-rated Beck hopelessness scale (BHS)21; the xxx item inventory of depressive symptomatology (IDS-C30), clinician rated version22; and the clinical global impression calibration (CGI) to appraise the global impression according to the clinician.

Then, patients received a outset twoscore infinitesimal intravenous infusion of ketamine (0.5 mg/kg) or placebo 0.9% (saline solution) in add-on to their current handling. This procedure has been used in most previous studies.12 A 2nd administration was performed 24 hours later (including during weekends or bank holidays). The pick of two infusions was based on available information at the time of protocol writing in 2013/2014.823 Moreover, at that fourth dimension, virtually protocols used a placebo, whereas after studies used midazolam.12 Usual care for these patients included a combination of admission to hospital, regular meetings with the healthcare staff (physicians, nurses), medication, individual and group psychotherapy, and family meetings.

Clinical evaluations were conducted at 40 minutes, ii hours, iv hours, day 1 (earlier the second infusion), twenty-four hours 2, and day three. They comprised the SSIs, CSSRS, PPP-VAS, BHS, IDS-C30, CGI, and an assessment of safety and side effects with the Young mania rating calibration (YMRS),24 patient rated inventory of side furnishings (PRISE),25 and cursory psychiatric rating scale (BPRS).26 Patients were then followed up until the end of calendar week 6, with assessments at day 4, calendar week two, week 4, and week 6.

Outcomes

The chief outcome was the rate of patients with a clinician rated SSI full score ≤three (that is, in current full suicidal remission) at twenty-four hours 3 for each treatment arm and in each diagnostic group. SSI is a calibration assessing suicidal ideation based on xix items scored 0 to two (maximum score 38).18 Here, we used the level of suicidal ideation on the day of assessment. Secondary outcomes at day iii were, for each arm and in each diagnostic group: rates of remission at intermediate time points; changes in SSI, BHS, PPP-VAS, IDS-C30, and CGI hateful scores betwixt baseline and day three; rates of suicide attempts (CSSRS) during the three day menstruation; and treatment side effects in each arm (YMRS, PRISE, and BPRS). At week half-dozen, secondary outcomes were the rates of total suicidal remission in both arms.

Protocol amendments

Details of changes to the original protocol are presented in tabular array S1. Briefly, changes were minor, including changes in investigators, biobank procedures (for time to come studies), extension of the inclusion flow to accomplish the targeted sample size, and stopping the use of the self-rated quick 16 item Inventory of Depressive Symptomatology to salve time, in addition to several questionnaires at 40 minutes, 2 hours, and 4 hours to reduce the burden of assessment.

Statistical analysis

This was a superiority trial. Calculation of sample size was washed with nQuery software version eight.7.2.0 (table S2). Based on available literature at the fourth dimension of the study formulation, the hypothesis was an absolute deviation of 45% resolution of suicidal ideation at mean solar day iii betwixt the two arms in each of the diagnostic groups (60% in the ketamine arm five fifteen% in the placebo arm). To test this difference with a power of 85%, a two sided α gamble of v% and taking into account the chance of α aggrandizement associated with multiple comparisons (n=iii), 52 patients were required for each diagnostic category (26 per arm), for a total of 156. A data monitoring committee oversaw the study.

Quantitative data were expressed equally hateful and standard deviation or median and interquartile range, co-ordinate to their distribution. Qualitative data were expressed as absolute number and frequency (%). Comparison between groups used, equally appropriate, Educatee's t, Wilcoxon's, Χtwo, or Fisher's tests. The rates of patients with SSI ≤three at day 3 were compared betwixt the 2 arms by a logistic regression model to take into account an arm by diagnostic grouping interaction to test heterogeneity. If the interaction term was meaning, the between arm comparison was performed within each of the diagnostic categories. Holm'south corrections were performed to accommodate for multiple comparisons. The associated odds ratios were estimated with 95% confidence interval with the profile likelihood method.

Linear mixed models were used to examine the effect of ketamine compared with placebo over time, on the different scores used every bit secondary endpoints, with patient considered as random effect. Time, drug, and fourth dimension by drug interaction were tested. Analyses were performed inside each of the diagnostic groups when interaction with arm was meaning. The associations between treatment, suicidal ideas, and psychological pain were explored with a mediation model. All included patients were analysed according to the intention-to-treat principle. A P value ≤0.05 was considered equally statistically significant. Statistical assay was performed with R 3.5.1 software (R Development Cadre Team, (2018). R Foundation for Statistical Computing, Vienna, Republic of austria).

Patient and public involvement

Patients and the public were non involved in the blueprint or conduct of this study, because their interest in the design of scientific studies is recent in France and was non customary when the study was started in 2013. As the benefits of public involvement are obvious, this arroyo volition be prioritised in our futurity studies. Moreover, patients volition be involved in the discussion and dissemination of the findings of this study.

Results

Patient characteristics

Between 13 April 2015 and 12 March 2019, 156 patients were recruited and randomised to ketamine (north=73) or placebo (n=83), stratified into three groups: bipolar disorder (n=26/26, respectively); depressive disorder (26/thirty); and other diagnoses (21/27; fig one). 1 centre (Center Hospitalier Universitaire, Nîmes) included 75.0% of all patients.

Fig 1

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Details of the participants' characteristics are shown in table 1 (and tables S3-S5 for characteristics of each diagnostic group). Of note, patients had a past history of a suicidal act in 67 (93.one%) of 72 participants (information for ane patient missing) in the ketamine arm, and in 70 (85.4%) of 82 participants (data for one patient missing) in the placebo arm. At inclusion, patients were severely suicidal in 71 (97.3%) of 73 participants in the ketamine arm and in 71 (86.6%) of 82 participants (data for one patient missing) in the placebo arm, based on the suicidality department of MINI 5.0 (x or more points on a 32 bespeak calibration). All patients remained in hospital at day 3. At weeks 2, 4, and half-dozen, rates of admission to infirmary in the placebo and ketamine arms were, respectively 53.iv%/41.8%, 34.iv%/31.7%, and 22.7%/xi.vii%.

Table ane

Baseline characteristics of the intention-to-care for population, by treatment grouping. Values are numbers (%) unless stated otherwise

Main outcomes at twenty-four hours 3

Past twenty-four hour period 3 (primary endpoint), two patients withdrew consent and 1 was lost to follow-upwardly (after the second infusion) in the placebo arm. On day 3, 46 (63.0%) of 73 patients in the ketamine arm and 25 (31.6%) of 79 patients (information for one patient missing) in the placebo arm had reached full remission of suicidal ideas (odds ratio three.7 (95% conviction interval 1.9 to seven.iii), P<0.001). These results were unchanged later on adjustment for sexual activity and presence of severe suicidal ideas (odds ratio 3.9 (ii.0 to vii.9), P<0.001) or antalgic utilise (3.seven (1.9 to 7.6), P<0.001). Change over time in rates of suicidal remission occurred by 40 minutes later infusion and persisted over the 3 day period (fig ii).

Fig 2

Fig two

Change in rates of suicidal remission over time within 72 hours of the first injection. Hither, suicidal remission corresponds to a score < 3 on the Beck scale for suicidal ideation, clinician rated version

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This issue differed according to the diagnostic group, with a pregnant interaction between arm and grouping, after adjustment according to sex activity and presence of severe suicidal ideas (treatment arm: t=14.7; df=1, P<0.001; diagnostic group: t=three.iii; df=2; P=0.2; interaction: t=vii.one; df=two; P=0.03): 84.half-dozen% (n=22) v 28.0% (n=7) in the bipolar disorder grouping (odds ratio 14.1 (3.0 to 92.2), P<0.001), 42.iii% (northward=11) 5 35.7% (n=10) in the depressive disorder grouping (one.3 (0.3 to 5.ii), P=0.vi), and 61.9% (n=13) v 30.8% (n=eight) in the other diagnoses group (3.seven (0.9 to 17.iii), P=0.07). Calculation the main effect of recruitment centre into the analyses did not alter the outcomes.

Secondary outcomes at day 3

Table S6 in the supplemental materials shows information on the detailed outcomes. We found significant differences (after adjustment for centre and diagnostic group) between the ketamine and placebo arms at day 3 in SSI median scores—both for the clinician rated (one.0 (interquartile range 0-8.0) five 8.0 (2.0-15.v), respectively; unstandardised regression coefficient β=−5.0 (95% confidence interval −7.7 to −two.3), P<0.001) and patient rated versions (median score 7.0 (4.0-12.0) v eleven.v (7.0-sixteen.ii); β=−2.5 (−four.v to −0.4), P=0.02)—and in scores of depression (17.4 (standard deviation 12.1) five 24.2 (12.seven); β=−half dozen.5 (−10.5 to −2.iv), P=0.002), psychological pain (3.seven (interquartile range 0.3-vi.three) v 5.0 (2.0-8.0); β=−1.two (−2.two to −0.1), P=0.03), hopelessness (9.0 (iv.0-15.0) v thirteen.0 (8.0-17.0); β=-2.5 (−iv.iv to −0.6), P=0.01), and global clinical impression, but not physical pain (0.i (0.0-iii.0) 5 0.5 (0.0-3.5); β=−0.1 (−1.0 to 0.8), P=0.8). During the first three days, one suicide try occurred in the ketamine arm and none in the placebo arm.

No increase in YMRS and BPRS scores was seen in any patient from any arm (table S6). Table 2 reports the main side effects during the showtime three days. All side effects were rated as small-scale, and all symptoms reported in tabular array two reduced significantly between the first assessment and day 4 (all P<0.05). Seventeen patients (23.3%) experienced at to the lowest degree one side consequence in the ketamine group versus vii (8.4%) in the placebo grouping. The most common side effects in the ketamine group were sedation (xi.0%), depersonalisation (ix.half dozen%), and nausea (6.8%).

Table 2

Reports of side furnishings in each treatment arm within the 72 hour flow

Finally, we tested the hypothesis that the improvement of suicidal ideation was mediated past its event on psychological pain, as assessed by the patient rated version of the SSI. The treatment was associated with a significant reduction in SSI scores after 72 hours (t=−ane.9, P=0.05, accounting for centre), only this association was weaker (t=−i.8, P=0.07) after accounting for psychological pain, while psychological pain remained highly associated with SSI scores (t=7.2; P<0.001), suggesting a mediation effect.

Outcomes at week 6

Betwixt day 4 and week 6 (written report cease), vii patients withdrew consent and 7 patients were lost to follow-upwards in the placebo arm. In the ketamine arm, one patient died from suicide (adamant by the oversight committee to be unrelated to the intervention), 4 withdrew consent, and viii were lost to follow-upwards. Therefore, lx (82.2%) patients of the 73 in the ketamine group and 66 (79.5%) patients of 83 in the placebo group completed the study.

Over the study, eight patients (9.viii%) in the placebo arm (data for one patient missing) and six patients (8.2%) in the ketamine arm attempted suicide (two v goose egg, respectively, in the bipolar disorder grouping; one v five in the depressive disorder group; and five v one in the other diagnosis group). Betwixt day iv and calendar week 6, the ketamine arm continued to have meliorate full suicidal remission than the placebo arm (69.five v 56.3% at week vi), although this was not pregnant at week 6 owing to reduced suicidality in the placebo group over time (odds ratio 0.8 (95% confidence interval 0.iii to 2.v), P=0.seven; fig 3). Results for each intermediate endpoint are reported in table S6.

Fig 3

Fig 3

Change in rates of suicidal remission over fourth dimension within half dozen weeks of the start injection. Hither, suicidal remission corresponds to a score < three on the Beck scale for suicidal ideation, clinician rated version

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Give-and-take

Master findings

This study confirmed in a large randomised controlled trial that ketamine is a fast acting, efficient handling of suicidal ideation. In this population at very loftier suicidal risk, 63.0% reached full remission at three days after two infusions in the ketamine group in comparison with 31.6% in the placebo group. This upshot was rapid, with 43.8% remission just ii hours afterward the first infusion versus 7.three% in the placebo group. Ketamine was well tolerated without severe side effects. Main side effects, including sedation, depersonalisation/derealisation, nausea, and dizziness, were of short duration and occurred in around x% or fewer participants. In improver, the effect persisted at six weeks in 69.five% of individuals treated with ketamine (versus 56.3% in those receiving placebo).

This study highlights a major moderating effect on primary mental disorders. A stiff outcome of ketamine versus placebo was found in the group with bipolar disorder, whereas the result was moderate and did not quite reach significance in the grouping with "other psychiatric disorders," and was not-significant in major depressive disorders. Results in bipolar disorder—a disorder associated with a high suicidal take chances and limited options to treat depression27—are highly encouraging and back up 2 previous small studies.828 Notably, no mood switch was seen in the 26 patients with bipolar disorder treated with ketamine. Results in individuals not fulfilling the criteria for a total major depressive episode (whether bipolar or major depressive disorders) also support the observation that ketamine is efficient independently from depressive episodes, as suggested by previous authors.29 This group comprised a substantial number of individuals with mail-traumatic stress disorder, dysthymia, and anxiety disorders (panic disorder, agoraphobia, generalised anxiety disorder). These patients would probably also have had personality disorders, although this was not formerly measured.

The not-pregnant outcomes in depressive disorders are more challenging to interpret. This grouping showed the highest placebo effect (36% v 28% in bipolar disorder and 31% in other diagnoses). This placebo outcome is likewise higher than that institute in a meta-analysis of ten trials analysing 157 suicidal patients with overall remission rates (clinician rated measures) of around xxx% in the control group.29 Moreover, the outcome of ketamine (42%) was lower than in the 2 other groups in our study (84% and 62%) and in the meta-analysis (around 55%).29 Our written report, therefore, might have lacked power to observe an effect in this particular group with depressive disorders. Additionally, 1 study of treatment resistant low suggests that repeated doses of ketamine might be necessary for some patients to achieve remission of astringent suicidal ideas.xxx Therefore, this group might be particularly heterogeneous, with both more patients sensitive to a placebo upshot and more patients requiring repeated ketamine infusions.

The persistence of the ketamine effect at six weeks of intake is not in line with previous studies101131 and the related meta-analysis,12 but those three studies together analysed simply 63 patients. More long term studies are needed.

Over the half-dozen week menses, 8.2% of patients in the ketamine arm and nine.8% in the placebo arm attempted suicide, including 1 fatal human activity. Detailed examination of these events in the intervention group showed that (a) none of them had exacerbated depression or suicidal ideation scores after infusion, suggesting that ketamine had no straight negative result; (b) all these patients were poor responders to ketamine during the first three days equally indicated by depression and suicidal ideation scores; and (c) some of them finally reached remission of suicidal ideas later several days, which might take led to decreased vigilance. Information technology must be remembered that the resolution of a suicidal crisis necessitates more than medication lonely. Psychological, social, and family intendance and support should always be combined with pharmacotherapy. Finally, this study was non designed to assess the benefits of ketamine for prevention of a suicidal human action, and larger studies and meta-analyses will exist necessary. Of note, a contempo review of 15 studies13 suggested that in the short term no more than suicidal acts occurred in the ketamine group than in the placebo group.

Overall, the tolerance of ketamine was good, as 3 quarters of patients had no side furnishings, and side furnishings were largely pocket-size and of brusk duration. This result is in line with a recent review of literature emphasising that tolerance of ketamine is proficient.32

Additional findings

Our study suggests that the beneficial consequence of ketamine on suicidal ideation could be mediated by an outcome on psychological pain. Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) too have high levels of mental pain.33 Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain. Indirect support for this suggestion is the observation that the effects of ketamine on depression might involve the opioid system34 (although this is controversial35), that buprenorphine—a μ opioid partial agonist—is also effective on suicidal ideas,36 and that mental pain has been associated with the nociceptin organisation.33

Limitations

Results should be interpreted in light of several limitations. Firstly, although this is a large written report and sufficiently powered, analyses within diagnostic groups were on smaller samples, which might explain both the large outcome size of ketamine in bipolar disorder, and the lack of significant differences in the depressive disorder group. Secondly, as ketamine can induce recognisable furnishings (depersonalisation, dizziness), masking might have been compromised for both the patients and the investigators, just this was not formally measured. It should, however, be noted that merely 9.6% of patients in the ketamine group experienced depersonalisation and four.1% dizziness (v 2.4% in the placebo group) while other side effects were unspecific and found in the placebo group. Midazolam has been used instead of placebo in a few studies and should exist considered every bit a suitable control in the future. Thirdly, the rapid resolution of suicidal ideas after receiving ketamine does not equate to a reduced risk of suicidal acts, notably later hospital belch. Indeed, the rates of suicide attempts during follow-upwardly were similar between the groups. Moreover, ketamine is a drug with a potential for abuse. Longer follow-up of larger samples will be necessary to examine benefits on suicidal behaviours and long term risks.

Determination

This large trial confirms that ketamine rapidly induces remission of severe suicidal ideation in adults, an effect persisting over 6 weeks in 2 thirds of patients. This effect seems to be dependent upon comorbid mental disorders. The tolerance was proficient. Long term benefits and prophylactic of ketamine must exist examined and drugs with different mechanisms of action will have to be investigated for non-responders.

What is already known on this topic

  • Ketamine is a promising drug to speedily decrease suicidal ideation inside minutes of intake, although testify is limited

  • Previous studies were conducted in samples of limited size with questionable methodology, including the fashion in which suicidal ideas were measured; or the fact that response (that is, a reduction of 50% of symptoms on a calibration) was ofttimes used in preference to remission (that is, a lack of symptoms)

  • The influence of comorbid mental disorders on the consequence of ketamine for reduction of suicidal ideation is unclear

What this study adds

  • Ketamine is confirmed as a safe in the brusque term and a apace efficient treatment of a suicidal crisis, particularly in patients with bipolar disorder, who have a high suicidal chance with express options for treatment

  • The analgesic effect of ketamine might explain its benefits on the reduction of suicidal ideation

  • Investigation of other drugs with different pharmacological mechanisms for the short term treatment of a suicidal crisis is warranted

Ideals statements

Ethical approval

Upstanding approval was obtained on eighteen July 2014 from the research ethics board "Comité de Protection des Personnes (CPP) Sud Méditerranée Iii" (ref: 2014.06.03 bis). This report was prospectively registered on the 20 November 2014 on https://world wide web.clinicaltrials.gov/ (NCT02299440) and is listed on EudraCT: 2014-001324-30. All patients gave their informed, written and signed consent earlier inclusion.

Information availability statement

Individuals' participant data that underlie the results reported in this commodity (after de-identification) will be available. The report protocol, statistical assay programme, and informed consent form volition also exist provided on request. Information volition be immediately available after publication, with no finish date. Data volition be provided to investigators whose proposed apply of the data has been approved by an contained review committee identified for this purpose for individual participant data meta-analysis or review. Proposals should be directed to pascale.FABBRO@chu-nimes.fr

Acknowledgments

We thank Fabrice Boulet, Aurélie Chopin, Jorge Lopez-Castroman, Antoine Giron, and Bérangère Gomaere (CHU Nîmes); Guillaume Pineau, Etienne Kimmel (CH St Anne, Paris); Emilie Olié, Lucille Villain (CHU Montpellier); and Vincent Jardon (CHU Lille) for their participation as investigators. We also thank Léonie Gazel for her function as project manager, Carey Suehs for help drafting the protocol, Stéphanie Salles for data management, and Sarah Kabani for proofreading the manuscript.

Footnotes

  • Contributors: MA conceived the study. MA and PF designed the written report and wrote the protocol. All authors provided feedback on protocol before implementation. CD performed the analyses. FJ wrote the first draft. All authors agreed on the terminal version. MA is the guarantor; he had total access to all the data in the study and takes responsibleness for the integrity of the data and the accuracy of the information analysis. The corresponding author attests that all listed authors run across authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: Funded by Program Hospitalier de Recherche Clinique National (PHRC-N) 2013. The report funder had no role in the study design; in the drove, analysis, and interpretation of data; in the writing of the written report; or in the decision to submit the article for publication. The researchers are contained of the funders and all authors had full admission to all the information (including statistical reports and tables) in the report and can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Competing interests: All authors take completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from PHRC-N 2013 for the submitted work; FJ has no declaration of interests for the past v years. PG received, during the past 5 years, fees for presentations at congresses or participation in scientific boards from Alcediag-Alcen, Angelini, GSK, Janssen, Lundbeck, Otsuka, SAGE, and Servier. We-H reports personal fees from EISAI, Janssen, Lundbeck, Otsuka, UCB, and Chugai. PC received speaker and consultation fees from Exeltis, Janssen, and Pfizer. GV is part of a scientific board for Janssen. RG has received compensation as a member of the scientific advisory lath of Janssen, Lundbeck, Roche, SOBI, and Takeda; he has served every bit consultant and/or speaker for Astra Zeneca, Boehringer-Ingelheim, Pierre Fabre, Lilly, Lundbeck, MAPREG, Otsuka, Pileje, SANOFI, Servier, LVMH and received compensation; and he has received research back up from Servier; cofounder and stock shareholder: Regstem. P-ML has received bounty as consultant and member of a scientific advisory lath for Janssen. LS declares fees for advisory lath, travel support activities of consultant and lecturer in the past 5 years received from Janssen, Lundbeck, and Otsuka; fees for advisory board, travel support activities of consultant, lecturer, and kinesthesia member in the by five years received from Eisai, Janssen, Lundbeck, Otsuka, Sanofi, Teva. MA declares fees from Astra Zeneca and Lundbeck, and has been invited to congresses past Janssen-Cilag, Otsuka, Lundbeck, Servier, and Astra Zeneca.

  • The pb writer affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the written report take been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: As the personal identifying information of participants has been removed from the report dataset, it is non possible to send the results of this report to participants. Findings will exist shared with clinicians and patients through national and international conferences (in psychiatry or suicidology), the French Suicidology Association (GEPS), the French national observatory on suicide (which includes professionals, and patient associations), and printing release.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

References

  1. ↵

    Globe Health Statistics. Monitoring wellness for sustainable development goals. 2016.

  2. ↵
  3. ↵
  4. ↵
  5. ↵
  6. ↵
  7. ↵
  8. ↵
  9. ↵
  10. ↵
  11. ↵
  12. ↵
  13. ↵
  14. ↵
  15. ↵
  16. ↵
  17. ↵
  18. ↵
  19. ↵
  20. ↵
  21. ↵
  22. ↵
  23. ↵
  24. ↵
  25. ↵
  26. ↵
  27. ↵
  28. ↵
  29. ↵
  30. ↵
  31. ↵
  32. ↵
  33. ↵
  34. ↵
  35. ↵
  36. ↵

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Source: https://www.bmj.com/content/376/bmj-2021-067194

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