The drug’s effect on suicidal ideation may be at least partially independent of its antidepressant effects, which could prove important for the approval of variants of ketamine for treating suicidal patients.
A single infusion of ketamine appears to significantly reduce suicidal thoughts in depressed patients in as little as one day, with benefits lasting for up to one week, according to a meta-analysis reported in AJP in Advance.
Moreover, although change in the severity of depressive symptoms was strongly correlated with change in suicidal ideation, after controlling for improvement in severity of depressive symptoms, ketamine’s effects on suicidal ideation remained significant.
“It’s exciting because we used a large enough patient sample … that we are able to find a specific effect of ketamine on suicidal ideation independent, or partially independent, from its effect on depression,” co-lead author Samuel T. Wilkinson, M.D., of the Department of Psychiatry and the Child Study Center at Yale School of Medicine told Psychiatric News. (Wilkinson shared first authorship on the paper with Elizabeth Ballard, Ph.D., of the National Institute of Mental Health [NIMH].)
Whether ketamine’s antisuicidal properties occur independently of its general antidepressant effects could have an impact on Food and Drug Administration approval of ketamine variants for treating suicidal ideation or behavior. (Ketamine is approved by the Food and Drug Administration as an anesthetic, but it is unlikely to be approved for psychiatric conditions, Wilkinson said.)
Wilkinson and colleagues searched MEDLINE using the terms “ketamine,” “NMDA receptor antagonist,” “ketamine-like,” or “rapid antidepressant” and “suicide,” “suicidality,” or “suicidal ideation” for articles published between January 1, 2000, and November 15, 2016. Eleven eligible trials were identified from 153 citations, and corresponding authors provided individual subject data on 298 patients who participated in the 10 ketamine trials included in the analysis. Patients in the control arm of the trials received either saline or midazolam, which is used as a preoperative sedative.
A total of 167 patients met criteria for baseline suicidal ideation. Ketamine reduced suicidal ideation more rapidly than was observed with the control treatments on the Montgomery-Åsberg Depression Scale and the Hamilton Depression Scale, as well as on patient self-reports, with significant benefits appearing as early as day 1 after treatment and extending up to day 7.
Ketamine has attracted much research interest as a potential treatment for major depression. A new meta-analysis shows a single infusion reduces suicidal ideation. Key findings include the following:
Ketamine produced large effect sizes in reduction of suicidal ideation for up to one week.
The effects of ketamine on suicidal ideation appear to be at least partially independent of the agent’s effects on depression.
Isolation of the specific effect on suicidal ideation could expedite approval of ketamine variants for treatment of suicidal patients.
The Bottom Line: The analysis supports the significant promise of ketamine for suicidal ideation, but its clinical use is premature barring further research on more diverse patient samples looking at effects of long-term exposure to the drug. After adjusting for change in severity of depressive symptoms over time, response to the use of ketamine remained significant regardless of whether clinician-administered or self-report outcome measures were used.
APA Director of Research Philip Wang, M.D., Dr.P.H., said the meta-analysis further supports the “significant promise” of ketamine as a potential treatment for suicidal ideation. “This is an important quantitative review because of both the fairly robust effect size and the suggestion that the anti-suicidality benefit may be independent of the improvement in depressive symptoms,” he told Psychiatric News.
He added that ketamine appears to work very rapidly. Wang recalled videotaped interviews of patients in clinical trials of ketamine when he was deputy director of NIMH. “I remember seeing a profoundly depressed patient,” he said. “Almost immediately after she received the ketamine infusion, you could see her expression dramatically brighten. It was remarkable.”
But Wang cautioned that despite the promise—and despite the growing availability of ketamine “infusion centers” —much is still uncertain about how ketamine achieves its benefits and the long-term effects of the medication. It is also used recreationally and may have addictive potential; and there is some evidence that overstimulation of the glutaminergic system, through which ketamine is believed to act, may have negative effects.
Wilkinson echoed Wang’s cautionary comments. There may be legitimate uses for ketamine in patients who have not responded to multiple antidepressant drug trials or to electroconvulsive therapy (ECT), but in general the clinical use of ketamine for suicidal thinking is premature until further research is done with a wide range of patients looking at possible effects of long-term exposure.
“The present analysis provides evidence drawn from the largest sample to date that ketamine reduces suicidal ideation partially independently of mood symptoms,” Wilkinson and colleagues wrote. “However, the specificity of this effect requires further exploration. … For ketamine to have a future as a potential anti-suicidal therapeutic in patients with a range of mood and anxiety disorders, studies specifically recruiting diverse populations must be conducted.”
Wang said some pharmaceutical companies are developing variants of ketamine that hopefully may retain the drug’s potential therapeutic effect, without some of the associated side effects. He said other studies are exploring if the drug could be used in much the same way as ECT is currently used—as a relatively rapid-acting, single-dose treatment, followed by adjunctive psychotherapies and mood-stabilizing medications.
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