Ketamine, an injectable anesthetic that has been shown to exert a rapid but short-lived antidepressant effect, may reduce suicidal ideation independently of a reduction in depressive symptoms, new research suggests.
Investigators at the National Institute of Mental Health in Bethesda, Maryland, distinguished the relationship of ketamine to reduced suicidal thoughts from its effect on depression and anxiety symptoms across 4 studies conducted in patients with treatment-resistant major or bipolar depression.
Although the reduction of suicidal ideation was correlated with improvements in mood, this new analysis showed that changes in mood and anxiety accounted for no more than 19% of the improvements on suicidal measures, including the Scale for Suicide Ideation items of the "wish to live" and "wish to die."
The study is "a first step in exploring how ketamine may impact suicidal thoughts, whether through depressive or anxiety symptoms," lead investigator Elizabeth Ballard, PhD, told Medscape Medical News.
The study was published online August 12 in the Journal of Psychiatric Research.
An N-methyl-D-asparate (NMDA) glutamate receptor antagonist, ketamine has made headlines in recent years because several studies have shown that it produces a rapid antidepressant effect in patients with unipolar and bipolar depression when delivered intravenously and, most recently, intranasally in spray form.
In addition, a recent study published in JAMA Psychiatry and reported by Medscape Medical News also suggests it may be a rapid treatment for posttraumatic stress disorder.
The researchers point out that suicide is a psychiatric emergency and that there are no approved medications to effectively treat suicidal ideation, noting that antidepressants can take weeks or months before they take effect.
"As a consequence, the 400,000 individuals who seek emergency treatment for suicidal thoughts and behavior each year often do not receive timely relief," the authors write.
Although it is known that ketamine has a rapid effect on depression and anxiety as well as suicidal thoughts, it is not clear whether this effect is independent or is a consequence of a reduction in depressive and anxiety symptoms.
An agent with rapid and specific effect on suicidal ideation might serve not only as an immediate intervention prior to the onset of antidepressants but also as an alternative pharmacologic model to lithium or clozapine, which, the researchers suggest, exert antiaggressive and anti-impulsive effects that "may be more suited to reducing suicide attempts than suicidal ideation."
To evaluate ketamine's effect on suicidal ideation, the investigators analyzed data from 4 independent, previously published clinical trials investigating the use of ketamine in 133 patients aged 18 to 65 years with treatment-resistant depression (major depressive disorder or bipolar depression), including a subset of 57 patients determined to have suicidal thoughts at baseline.
The investigators evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale, the Scale for Suicidal Ideation, the Beck Depression Inventory, and the Hamilton Anxiety Rating Scale.
All participants received a single subanesthetic infusion of ketamine (0.5 mg/kg) during a 40-minute period. Investigators assessed the impact of the drug at 230 minutes and found that correlation between changes in suicidal ideation and changes in depression ranged from 0.23 to 0.44 (P < .05), accounting for up to 19% in the variance of ideation change.
Dr. Ballard noted that in order to conclude that ketamine reduces suicidal thoughts, "we still need a randomized controlled trial of ketamine in acutely suicidal patients."
However, if it does turn out that ketamine decreases suicidal ideation, it will have "important implications for both the neurobiological profile of suicidal thoughts and the treatment of suicidal patients."
The prospect of an agent with rapid and specific antisuicidal effect is welcome not only because of a shorter time to onset than traditional antidepressants but also, as the investigators note, because "not all suicidal ideation and behavior are explained by mood and anxiety symptoms alone. Many individuals think about, attempt and die by suicide outside the context of a depressive or anxious episode."
Commenting on the findings for Medscape Medical News, James Murrough, MD, Icahn School of Medicine at Mount Sinai, New York City, whose own group has led much of the ketamine research, said the study "went a long way toward addressing the hypothesis that ketamine has specific antisuicidal effects, so I think it's an important contribution to the literature."
Dr. Murrough agreed with Dr. Ballard that confirming an antisuicidal effect will require studies to be conducted in patients who are suicidal, rather than in populations identified only as having affective disorders.
"The definitive tests will still have to be done in patient populations that have a higher degree of those specific symptoms under study," he said.
He went on to suggest that short-acting ketamine might prove useful "to buy time" in an emergency, and possibly to serve as a protective bridge when starting an antidepressant that could actually increase suicide risk during the initial treatment window.
However, he cautioned against expecting that a rapid-acting, short-lived antisuicidal drug, without effective long-term treatment, would reduce an individual's overall risk for suicide.
"The reality is that suicide risk is not something that goes away necessarily very quickly," he said.
Dr. Ballard reports no relevant financial relationships. Complete disclosures of the other authors can be found in the original article. Dr. Murrough reports no financial relationships relevant to this study.
J Psychiatr Res. Published online August 12, 2014. Abstract
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Cite this: Ketamine May Curb Suicidal Thoughts - Medscape - Aug 27, 2014.