Two Intravenous Injections of Ketamine at 24h-Interval for the Acute Treatment of Severe Suicidal Ideas: A Randomised Double-Blind Placebo-Controlled Superiority Trial

Abstract

Background: Ketamine is suggested to have rapid-onset anti-suicidal benefits. This must be confirmed in a large sample, alongside a potential moderating effect of comorbid mental disorders. Methods: Double-blind superiority trial comparing ketamine (0•5mg/kg) to placebo, conducted in seven teaching hospitals in France (KETIS). Participants aged 18 and older with current suicidal ideation were electronically randomised and stratified by centre and main diagnosis: bipolar, depressive, or other (non-psychotic) disorders. Two 40-min intravenous injections were administered at baseline and after 24 hours in addition to usual treatment. The primary outcome was the rate of patients in full suicidal remission at Day 3, according to clinician-rated Scale for Suicidal Ideation total score < 3. Analyses were conducted on an intention-to-treat basis. Registered on ClinicalTrials.gov (NCT02299440)(trial closed). Findings: 156 participants were recruited between April 13, 2015 and March 12, 2019 and randomised to placebo (n=83) or ketamine (n=73). More patients reached full remission of suicidal ideas at Day 3 in the ketamine than placebo arm (63•0 vs. 31•6%). However, this effect differed according to diagnoses (treatment: p<0•001; interaction: p=0•02): bipolar (Odds Ratio (OR 95% confidence interval)=14•1 (3•0 – 92•2), p=0•0005), depressive (OR=1•3 (0•3 – 5•2), p=0•6), or other disorders (OR=3•7 (0•9 – 17•3, p=0•07)). Side effects were limited. No manic or psychotic symptom was observed. Moreover, a mediating effect of mental pain was found. At Week 6, the ketamine arm remained superior to placebo for full suicidal remission (69•5 vs. 56•3%). Interpretation: This study confirmed the rapid, safe and persistent benefits of ketamine for acute care in suicidal patients. However, comorbid mental disorders appear to be important moderators. An analgesic effect on mental pain could explain ketamine’s anti-suicidal effects. Clinical Trial Registration Details: This study is listed on www.ClinicalTrials.gov (NCT02299440), and EudraCT: 2014-001324-30 (trial closed). Funding Information: The study was funded by a national public grant (PHRC-N 2013). Declaration of Interests: FJ has no declaration of interests for the last 5 years. PG received during the last 5 years fees for presentations at congresses or participation in scientific boards from Alcediag-Alcen, Angelini, GSK, Janssen, Lundbeck, Otsuka, SAGE and Servier. Wissam El-Hage 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 board of Janssen, Lundbeck, Roche, SOBI, Takeda. He has served as 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 support from Servier. Co-founder and stock shareholder: Regstem. PM has received compensation as consultant and member of a scientific advisory board for Janssen. LS declares fees for advisory board, travel support activities of consultant and lecturer in the last 5 years received from Janssen, Lundbeck and Otsuka. PML declares fees for Advisory board, travel support activities of consultant, lecturer and faculty member in the last 5 years received from Eisai, Janssen, Lundbeck, Otsuka, Sanofi, Teva. MA declares fees from Astra Zeneca and Lundbeck, and has been invited to congresses by Janssen-Cilag, Otsuka, Lundbeck, Servier and Astra Zeneca. CD and PF have no conflicts of interests to declare Ethics Approval Statement: Ethics approval was obtained on July 18, 2014 from the Research Ethics Board “Comite de Protection des Personnes (CPP) Sud Mediterranee III”.All patients gave their informed, written and signed consent before inclusion.