Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder

This open-label study (n=34) investigated the effects of ketamine (35mg/70kg) on suicidal ideation and sleep rhythm in patients with (bipolar) depression and found that patients with less post-infusion nocturnal wakefulness exhibited an antisuicidal response to ketamine, compared to patients who were wakeful at night and continued suicidal ideation.

Abstract

“Objective Insomnia and disrupted sleep are associated with increased risk of suicide. The N-methyl-d-aspartate antagonist ketamine has been associated with reduced suicidal thoughts, but the mechanism of action is unknown. This study sought to evaluate differences in nocturnal wakefulness in depressed individuals who did and did not have an antisuicidal response to ketamine.

Methods Thirty-four participants with baseline suicidal ideation diagnosed with either DSM-IV major depressive disorder (n = 23) or bipolar depression (n = 11) between 2006 and 2013 completed nighttime electroencephalography (EEG) the night before and the night after a single ketamine infusion (0.5 mg/kg over 40 minutes). Suicidal ideation was assessed at baseline and the morning after ketamine infusion via several measures, including the Hamilton Depression Rating Scale suicide item, the suicide item of the Montgomery-Asberg Depression Rating Scale, and the first 5 items of the Scale for Suicide Ideation. A generalized linear mixed model evaluated differences in nocturnal wakefulness, as verified by EEG, between those who had an antisuicidal response to ketamine and those who did not, controlling for baseline nocturnal wakefulness. Results were also compared to the sleep of healthy controls (n = 22).

Results After analyses adjusted for baseline sleep, participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion compared to those without an antisuicidal response (F1,22 = 5.04, P = .04). Level of nocturnal wakefulness after antisuicidal response to ketamine did not differ significantly from nocturnal wakefulness in the control sample but did differ at a trend level (F1,40 = 3.15, P = .08).

Conclusions Reductions in wakefulness following ketamine may point to a biological mechanism underlying the effect of ketamine on suicidal ideation.“

Authors: Jennifer L. Vande Voort, Elizabeth D. Ballard, David A. Luckenbaugh, Rebecca A. Bernert, Erica M. Richards, Mark J. Niciu, Lawrence T. Park, Rodrigo Machado-Vieira, Wallace C. Duncan & Carlos A. Zarate

Summary

Ketamine, an N-methyl-D-aspartate antagonist, was associated with reduced suicidal thoughts in depressed individuals.

Thirty-four participants with baseline suicidal ideation completed nighttime electroencephalography the night before and the night after a single ketamine infusion. The results were compared to the sleep of healthy controls.

Participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion compared to those without an antisuicidal response.

In 2012, 40,600 suicides occurred in the United States. Clozapine is the only medication with a specific FDA indication for reducing the risk of recurrent suicidal behavior in those with schizophrenia.

Research has shown that disrupted sleep is associated with increased risk of suicide death in both adults and adolescents, and this association is often independent of depressive symptoms. Few studies have used objective measures to evaluate sleep in those with suicidal thoughts.

Investigators have worked to understand how psychotropic medications affect sleep, particularly antidepressants. However, few studies have examined how sleep changes relate to clinical antidepressant response. In treatment-resistant patients with current suicidal ideation experiencing a major depressive episode, nocturnal wakefulness was associated with a reduced suicidal response to ketamine. This relationship was maintained after adjusting for age, gender, diagnosis, and severity of depression.

Patient Population

This study was a secondary analysis of 34 patients with suicidal ideation and treatment-resistant depression who participated in a series of clinical trials to evaluate the efficacy of ketamine between 2006 and 2013. All patients were currently experiencing a major depressive episode.

All MDD patients were medication-free for at least 2 weeks, and bipolar disorder patients were only taking lithium or valproate at therapeutic levels.

A subset of patients received riluzole the night after receiving open-label ketamine infusion. Baseline sleep data were obtained for 22 healthy control subjects, who had no current or past psychiatric diagnoses or first-degree relatives with DSM Axis I disorders.

Study Design

All patients received intravenous ketamine hydrochloride (0.5 mg/kg over 40 minutes) and underwent whole-night polysomnography (PSG) the night before and the night after ketamine infusion. Hourly minutes awake were calculated for each hour of the night from midnight until 04:59 AM.

Assessments

The HDRS, MADRS, and SSI5 were administered 60 minutes before ketamine infusion and in the morning of the day after ketamine infusion. The SSI5 was included in the analysis because previous analyses found that it is particularly sensitive to rapid changes in suicidal thoughts.

Data were limited to participants who reported suicidal ideation at baseline and no suicidal thoughts 1 day after ketamine infusion. A score of 2 or more was considered to be “any suicidal ideation”.

We used T tests and 2 tests to evaluate possible baseline demographic, clinical, and sleeprelated differences between suicide responders and nonresponders to ketamine. A negative binomial generalized linear mixed model with a log linking function was used to evaluate differences in nocturnal wakefulness between suicide responders and nonresponders the night after ketamine infusion. A generalized linear mixed model was used to compare waking in suicide responders to healthy controls, and psychiatric diagnosis was adjusted for as well as an interaction with antidepressant response.

The night after ketamine infusion, suicide responders to ketamine demonstrated fewer minutes of nocturnal wakefulness than nonresponders, with a time-by-responder interaction at a trend level.

When the sample was limited to 23 suicidal participants who had only received ketamine (and not riluzole), overall differences were comparable. However, the time-by-responder interaction was significant, and the effect size for overall nocturnal wakefulness was large in responders.

The mean minutes awake by hour of night in suicide responders and nonresponders to ketamine are presented in Figure 3. A generalized linear mixed model found a trend between suicide responders and healthy controls.

We confirmed the results of the MADRS study by comparing the results using the SSI5 and the MADRS suicide item. The SSI5 had a smaller sample size.

We evaluated the impact of diagnosis on the results using the HDRS suicide item, and found that the suicide response was still significant after adjusting for diagnosis and antidepressant response.

DISCUSSION

Depressed patients who experienced an antisuicidal response to ketamine had decreased nocturnal wakefulness the night after ketamine compared to those with no antisuicidal response. This finding suggests that increased NMDA receptor throughput and/or increased synaptogenesis may be involved in the antisuicidal effect of ketamine.

Ketamine may reduce suicidal ideation by decreasing brain-derived neurotrophic factor (BDNF) release and by affecting regional cerebral glucose metabolism in the infralimbic cortex, but these effects are not entirely driven by its antidepressant effects.

Ketamine may have antisuicidal effects via multiple mechanisms, including increased slow-wave sleep and increased BDNF levels, as well as a connection between low-grade brain inflammation with glutamate agonism and suicidal ideation/behavior.

This study has several strengths, including objective measurement of sleep changes, use of several metrics to measure suicidal ideation, and healthy controls. Despite several limitations, the study found that improving disrupted sleep and suicidal ideation with ketamine was associated with a decreased risk of suicide. Further studies are needed to evaluate the relationship between sleep and suicidal ideation in patients with treatment-resistant depression.

This study investigates how the rapid-acting, antisuicidal effects of ketamine may be related to night-time wakefulness patterns during sleep. The results are consistent with previous time-of-day studies showing that increased wakefulness between midnight and 4:59 AM is associated with increased suicidal ideation the next day.

Ketamine may have antisuicidal effects, and participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion.

Figure 1.

Participants completed an adaptation sleep study before their first recorded polysomnography and a second recorded polysomnography after their ketamine infusion.

Participants who had an antisuicidal response to ketamine had a shorter wakefulness pattern than participants who did not.