Ketamine Rapidly Reduces Suicidal Ideation, But How Long Does This Last?

For patients with severe or treatment-resistant depression, waiting several weeks or longer for an antidepressant to take effect can be excruciating.  For patients with suicidal ideation, this represents a period of increased vulnerability.  The dissociative anaesthetic ketamine, an antagonist at the N-methyl-d-aspartate (NMDA) receptor, has been a promising new treatment for depression, in that ketamine can provide almost immediate relief, even in those who have not responded to traditional antidepressants.  In addition, ketamine seems to have a strong anti-suicidal effect.  

But How Long Do the Beneficial Effects of Ketamine Last?

In a recent study, Anna Feeney, MD and colleagues from the Clinical Trials Network and Institute in the MGH Department of Psychiatry assessed the effect of a single dose of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). 

Adult patients with TRD and current depressive symptoms despite ongoing, stable, and adequate antidepressant treatment were recruited for this study. Participants were randomized to receive either a single infusion of IV ketamine (0.1 mg/kg, 0.5 mg/kg or 1.0 mg/kg doses) or an active placebo infusion of IV midazolam. Suicidal ideation was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days after the infusion.  Clinically significant suicidal ideation was defined as a MADRS suicide item score of ≥ 2. 

At baseline, 40 out of 60 patients who received IV ketamine and 16 out of 19 patients who  received IV midazolam reported clinically significant suicidal ideation at baseline.  These 56 patients were included in the analysis of changes in suicidal ideation over time. 

At day 3, 22 of 40 (55.0%) of participants receiving IV ketamine no longer reported clinically significant suicidal ideation, compared to 7 out of 16 (43.8%) of those receiving IV midazolam.  

On day 30 post-infusion, the mean suicide scores of the two groups differed significantly from each other; the IV ketamine group had a lower mean score than controls (2.03 ± 1.59 vs. 3.00 ± 1.41, p = 0.049). 

Looking only at patients who experienced a recuction in suicidal ideation at day 3 (those with a suicide score of ≥ 2 at baseline and < 2 at day 3), the researchers found that the two groups (ketamine vs. placebo) did not differ significantly in terms of mean score changes at days 3, 5, 7, 14 or 30. In both treatment groups, recurrence of suicidal ideation was common.  However, on day 30, recurrence of suicidal ideation in participants who received IV ketamine (45.5%) occurred less frequently than in participants who received IV midazolam placebo (71.4%).

Clinical Implications

The findings of this study indicate that while a single infusion of IV ketamine may reduce suicidal ideation in patients with TRD out to 30 days after infusion, early anti-suicidal effects appear to diminish rapidly. (The individual groups were too small to compare different doses of ketamine.) These findings are consistent with previous studies indicating that the antidepressant effects of ketamine wane over time. 

While a single dose of ketamine may not offer a “cure” for severe depression, the current study indicates that a single infusion of ketamine (or short-term treatment) may be useful as an adjunct to standard treatments in patients with severe depression and suicidal ideation.

Feeney A, Hock RS, Freeman MP, Flynn M, Hoeppner B, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, Debattista C, Ionescu DF, Fava M, Papakostas GI.  The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study. Eur Neuropsychopharmacol. 2021 Jun 2;49:122-132.

Papakostas GI.  Maintaining Rapid Antidepressant Effects Following Ketamine Infusion: A Major Unmet Need.  J Clin Psychiatry. 2020 Feb 4; 81(2):19r12859.