Ketamine Fast, Effective for Suicidal Crises

Megan Brooks

February 10, 2022

Ketamine is a rapid and effective treatment for suicidal ideation and has a "major" moderating effect based on the primary mental health diagnosis, results of a large randomized controlled trial shows.

In addition, a strong effect of ketamine was observed in patients with bipolar disorder, "whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was non-significant in those with major depressive disorders," the researchers write.

"We assessed for the first time in the same study the effect of ketamine on three a-priori defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses," study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, France, told Medscape Medical News.

"This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder," Jollant added.  

The study was published online February 2 in The BMJ.

Swift, Full Remission

The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.

They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment. 

The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0 to 2 (maximum score, 38).

"We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear," said Jollant.

They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs 32%; odds ratio [OR], 3.7; 95% CI, 1.9 - 7.3; P < .001).

This anti-suicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors report.

The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0 - 92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3 - 5.2;  P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9 - 17.3; P = .07).

At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly vs placebo (69.5% vs 56.3%; OR, 0.8; 95% CI, 0.3 - 2.5; P = .7).

The researchers note the beneficial effect of ketamine on suicidal ideation could be mediated by an effect 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) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain," they write.

Ketamine’s side effects were "limited" with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.

The investigators acknowledge that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is "challenging to interpret."

They point out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.

A New Perspective on Ketamine

In an accompanying editorial, Riccardo De Giorgi, Wellcome Trust doctoral training fellow, Department of Psychiatry, University of Oxford, United Kingdom, said the study challenges current thinking about ketamine.

The "unexpected" outcome (no benefit) in the depressive group "perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine," De Giorgi writes.

"In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder," De Giorgi points out.

"While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine," De Giorgi writes.

"Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts," he concludes.

Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Jollant and De Giorgi have disclosed no relevant financial relationships.

BMJ. Published online February 2, 2022. Full text, Editorial

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