Effects of Ketamine Versus Midazolam on Neurocognition at 24 Hours in Depressed Patients With Suicidal Ideation

In this double-blind trial (n=78) depressed patients with suicidal ideation were administered either ketamine or the benzodiazepine, midazolam. Ketamine produced rapid improvement in suicidal ideation and mood in comparison to midazolam and had positive effects on measures of neurocognition. However, improvements in neurocognition were not correlated with changes in depression, suicidal thinking, or general mood.

Abstract

Objective: Subanesthetic ketamine rapidly reduces depressive symptoms and suicidal ideation in some depressed patients. Its effects on neurocognitive functioning in such individuals with significant suicidal ideation is not well understood, even though certain neurocognitive deficits are associated with suicide behavior beyond clinical symptoms.

Methods: In this study, depressed patients with clinically significant suicidal ideation (n = 78) underwent neuropsychological testing before and 1 day after double-blind treatment with intravenous ketamine (n = 39) or midazolam (n = 39). A subgroup randomized to midazolam whose ideation did not remit after initial infusion received open ketamine and additional neurocognitive testing a day after this treatment. The primary outcome was change in performance on this neurocognitive battery. The study was conducted between November 2012 and January 2017.

Results: Blinded ketamine produced rapid improvement in suicidal ideation and mood in comparison to midazolam, as we had reported previously. Ketamine, relative to midazolam, was also associated with specific improvement in reaction time (Choice RT) and interference processing/cognitive control (computerized Stroop task)-the latter a measure that has been associated with past suicide attempt in depression. In midazolam nonremitters later treated with open ketamine and retested, reaction time and interference processing/cognitive control also improved relative to both of their prior assessments. Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood.

Conclusions: Overall, ketamine was found to have a positive therapeutic effect on neurocognition 1 day after treatment on at least 1 measure associated with suicidal behavior in the context of depression. Results suggest additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior.

Authors: John G. Keilp, Sean P. Madden, Julia E. Marver, Abigail Frawley, Ainsley K. Burke, Mohammad M. Herzallah, Mark Gluck, J. John Mann & Michael F. Grunebaum

Notes

Ketamine is the most widely accessible and utilized psychedelic. The off-label use of ketamine for treating mental health disorders such as depression and anxiety has soared in recent years as a plethora of ketamine clinics have emerged across the globe. Although evidence-based research is accompanying this increase in use, we still have a lot to learn about how ketamine exerts its therapeutic effects and how it compares to conventional treatments.

In the present study, researchers compared the effects of ketamine in depressed patients with suicidal ideation to that of midazolam and explored the ensuing effects on neurocognitive function. Midazolam is a benzodiazepine that is commonly used as an anaesthetic. In this double-blind study, participants received intravenous ketamine (n=39) or midazolam (n=39).

Main findings

• Ketamine produced rapid improvement in suicidal ideation and mood in comparison to midazolam.
• Ketamine was associated with improvements in specific reaction time and interference processing/cognitive control.
• Patients who had received midazolam but had not remitted were treated with ketamine at a later date. Similar neurocognitive effects seen in the original ketamine group were observed.

The findings of the present study suggest that ketamine has a positive on certain measures of neurocognition and reduces suicidal ideation in patients who are depressed. The onset of the effects elicited by ketamine was much more rapid and ultimately, more pronounced than that of midazolam. Such findings are important to advance our understanding of ketamine and are hugely beneficial to this particularly vulnerable patient group.

Summary

Subanesthetic ketamine reduces depressive symptoms and suicidal ideation in some depressed patients, but its effects on neurocognitive functioning are not well understood.

In this study, depressed patients with clinically significant suicidal ideation underwent neuropsychological testing before and 1 day after double-blind treatment with intravenous ketamine or midazolam.

Blinded ketamine improved suicidal ideation and mood in comparison to midazolam, and improved reaction time and interference processing/cognitive control in midazolam nonremitters, but not in depression, suicidal thinking, or general mood.

Ketamine had a positive therapeutic effect on neurocognition 1 day after treatment in depressed patients at risk for suicidal behavior.

We hypothesized that baseline cognitive slowing would correlate with therapeutic response to ketamine.

Patients who initially received blinded midazolam but did not show a clinical response were assessed a third time, 1 day after infusion, to determine if neurocognitive functions affected by ketamine during the blinded infusion were similarly affected after open ketamine.

Subjects

Participants were 78 individuals with major depressive disorder and clinically significant suicidal ideation. Two subjects were dropped for neuropsychological analyses, and all participants signed informed consent.

Instruments

The study included the 24-item Hamilton Depression Rating Scale (HDRS) and Beck Scale for Suicidal Ideation (SSI). Patients who did not respond to midazolam were offered an open ketamine infusion the next day.

Statistical Analyses

Neurocognitive performance was compared between the two drug assignment groups from baseline to day one, using a general linear model. Significant main effects and interactions were examined in univariate comparisons of individual tests, across assessment point and drug assignment.

Correlations With Clinical Response

Baseline Buschke SRT immediate performance correlated with the decline in HDRS score, but not with change in HDRS, SSI, or POMS scores. All scores improved on day 3 relative to baseline.

Neurocognitive Changes After Open Ketamine

There was overall improvement across all tests and assessment days, with the average z score being significantly better on day 3 than on day 1.

Day 3 performance was improved relative to day 1 and baseline on Choice RT, WAIS-III Digit Symbol, Stroop Interference, Letter and Category Fluency, but not on Buschke SRT Immediate or Delayed.

DISCUSSION

Depressed patients with clinically significant suicidal effects on suicidal ideation improved selectively after subanesthetic ketamine infusion on measures of response time and interference processing/cognitive control. These neurocognitive effects may reduce suicide risk in ways other than reduction in ideation and depressive symptoms alone.

Ketamine may enhance prefrontal cortex function and improve neurocognitive tasks in rodents. It may also improve decision making in human studies with substance abusing populations.