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 nonsignificant in those with major depressive disorders,” the researchers wrote.
“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, said in an interview.
“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,” Dr. Jollant added.
The study was published online Feb. 2, 2022, 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 0-2 (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 Dr. 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, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
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 versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted 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 wrote.
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 acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed 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.