Ketamine Promising for Suicidal Ideation in Major Depressive Disorder

Ketamine may represent an effective adjunct therapy in the treatment of suicidal ideation in patients with major depressive disorder (MDD), according to the results of a randomized clinical trial published in the American Journal of Psychiatry.¹

No recommendation is currently available for the treatment of suicidal ideation in patients with MDD, mainly due to the lack of supporting evidence. In its 2010 practice guidelines, the American Psychiatric Association recommended treating patients with MDD and suicidal ideation with electroconvulsive therapy and psychotherapy,² and emphasized the lack of evidence supporting the efficacy of antidepressants in lowering suicide rates in this patient population.³ Although fluoxetine and venlafaxine were found to reduce suicidal thoughts in an adult population through a decrease in depressive symptoms, these effects were not visible until weeks after treatment initiation, a timeline suboptimal for patients with suicidal ideation who require rapid relief.⁴

Ketamine, an antagonist of N-methyl-D-aspartate glutamate receptors, has been widely used as an anesthetic in the past decades. More recently, single injections of this compound at subanesthetic doses have been shown to have fast antidepressant and anxiolytic effects lasting from a few days to 2 weeks, including in patients with treatment-resistant depression.⁵ This antidepressant effect of ketamine is thought to be mediated — in addition to its effect on descending glutamatergic pathways — by its binding to dopamine D2 receptors, leading to an upregulation in dopamine release.^5,6

The current clinical trial included 80 participants with MDD —  according to the Diagnostic and Statistical Manual of Mental Disorders IV criteria — with a voluntary admission to an inpatient research unit at New York State Psychiatric Institute  with a score ≥16 on the Hamilton Depression Rating Scale (HAM-D).¹ These participants were considered to exhibit “clinically significant suicidal ideation” — as indicated by a score ≥4 on the 0 to 20 Scale for Suicidal Ideation (SSI) — and were randomly assigned to receive an intravenous infusion of 0.5 mg/kg racemic ketamine hydrochloride (n=40; 55% women; 87.5% white; mean age, 38.4), or an infusion of 0.02 mg/kg midazolam in saline for 40 minutes (n=40; 65% women; 97.5% white; mean age, 40.7). Patients could remain on their current pharmacologic treatment for psychiatric disorders during the trial with the exception of benzodiazepines, which had to be discontinued 24 hours before treatment. Baseline characteristics in terms of demographics, history of substance use disorder, ratings of depression and suicidal ideation, and medication history were similar in both groups.

The trial’s primary outcome was an SSI score 24 hours after treatment. Secondary outcomes included ratings of global depression (evaluated with the HAM-D, the Beck Depression Inventory, and the Profile of Mood States [POMS]) and assessment of anxiety. Due to the dissociative effects of ketamine, finding a suitable compound to be used as a control for the drug in clinical studies was challenging. The investigators chose midazolam, a schedule IV sedative with psychoactive properties and a half-life comparable to that of ketamine, with no known antidepressant or antisuicidal effects.

Study participants in the ketamine group had reduced suicidal ideation 24 hours after infusion compared with patients in the midazolam group (4.96 point difference in SSI scores; 95% CI, 2.33-7.59; P <.001) and greater reductions in SSI scores 230 minutes after infusion (9.69 points vs 5.41 points, respectively; P <.001). Study participants who still had suicidal ideation 1 day after treatment had greater improvements in suicidal desire and ideation subscale in the ketamine vs midazolam group (P =.049) but similar scores on the SSI planning subscale. Depressive symptoms were improved to a greater degree at day 1 by the ketamine vs midazolam infusion (total mood disturbance evaluated with POMS, P =.023; depression subscale, P =.018).

Observed improvements in SSI scores and depression ratings with the ketamine infusion were sustained for a period of 6 weeks. The main adverse events associated with the ketamine treatment were mild to moderate and included transient increases in systolic and diastolic blood pressure and dissociative symptoms.

“A single adjunctive subanesthetic ketamine infusion was associated with a clinically significant reduction in suicidal ideation at day 1 that was greater than with the midazolam control infusion,” concluded the investigators, an effect which persisted for at least 6 weeks.

References

1. Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2017:appiajp201717060647.
2. Gelenberg AJ, Freeman, MP, Markowitz JC, et al. Practice guideline for the treatment of patients with major depressive disorder. Third edition. 2010. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed January 22, 2018.
3. Jacobs DG, Baldessarini RJ, Conwell Y, et al. Practice guideline for the treatment of patients with suicidal behaviors. Third edition. 2010. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/suicide.pdf. Accessed January 22, 2018.
4. Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):580-587.
5. Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders?. Neuropsychopharmacology. 2015;40(5):1307.
6. Tan S, Lam WP, Wai MS, Yu WH, Yew DT. Chronic ketamine administration modulates midbrain dopamine system in mice. PLoS ONE. 2012;7(8):e43947.