This open-label study (n=323) with repeated IV ketamine infusions (4x, 35mg/70kg) finds that sleep is a partial mediator to the improvements in depression (TRD), similar effects were found on reducing suicidal ideation (SI).

Abstract

“Sleep disturbances are commonly reported in patients with treatment-resistant depression (TRD). Available data have shown that intravenous (IV) ketamine is an effective treatment for patients with TRD and growing data suggest ketamine may improve overall sleep architecture. In the present study, we evaluated whether changes in sleep symptoms mediated the anti-depressive and/or anti-suicidal effects of IV ketamine and whether improvement in sleep correlated with a higher likelihood of achieving response or remission. Adults with TRD received four infusions of IV ketamine at a community-based clinic. Total depressive symptom severity was measured with the Quick Inventory Depressive Symptoms Self-Report 16-Item (QIDS-SR₁₆) at baseline and was repeated across four infusions. Suicidal ideation (SI) and four sleep symptoms were measured using the SI item and the five sleep items on the QIDS-SR₁₆. A total of 323 patients with TRD received IV ketamine. Self-reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking, and total sleep were significant partial mediators to the improvements observed in depression severity. Similarly, insomnia, night-time restlessness, early morning waking and total sleep improvements mediated the reduction of IV ketamine on SI. All sleep items, except for hypersomnia, were associated with an increased likelihood of achieving response or remission. Notably, each point improvement in total sleep score was significantly associated with achieving responder/remitter status (odds ratio 3.29, 95% confidence interval 2.00–5.41). Insomnia, sleep restlessness, early morning waking and total sleep improvements were significant mediators of antidepressant and anti-suicidal improvements in patients with TRD receiving IV ketamine.“

Authors: Nelson B. Rodrigues, Roger S. McIntyre, Orly Lipsitz, Danielle S. Cha, Bing Cao, Yena Lee, Hartej Gill, Leanna M. W. Lui, Wiesław Cubała, Roger Ho, Margarita Shekotikhina, Kayla M. Teopiz, Mehala Subramaniapillai, Kevin Kratiuk, Rodrigo B. Mansur & Joshua D. Rosenblat

Summary

Adults with treatment-resistant depression received four infusions of IV ketamine at a community-based clinic. Sleep symptoms were measured at baseline and across four infusions, and improvement in sleep symptoms correlated with a higher likelihood of achieving response or remission. Patients with TRD who received IV ketamine reported improvements in insomnia, night-time restlessness, hypersomnia, early morning waking and total sleep, which were significant mediators of antidepressant and anti- suicidal improvements.

Sleep disturbances are commonly reported by patients with major depressive disorder and bipolar disorders, and are associated with significant multi-domain disturbances across mood disorders.

Sleep disturbances are associated with suicidal ideation and attempts, especially among adolescents, independent of depression severity. Melatonin receptor agonists, bright-light therapy, and sleep deprivation therapy are effective at remitting depressive symptoms.

Conventional antidepressants do not adequately treat major depressive episodes, and approximately one-third of patients fail to experience adequate symptom relief with available monoaminergic-based treatments and/or chronotherapies.

Ketamine has been shown to be an effective treatment for patients with treatment-resistant depression. Ketamine is thought to affect the circadian clock and may normalise the phase-shifted circadian rhythm.

Ketamine’s impact on sleep architecture was consistently associated with cognition and mood, suggesting that ketamine likely exerts multi-modal effects across dispa rate domains commonly affected in mood disorders.

2.1 | Participants and study design

All participants received IV ketamine treatment at the Canadian Rapid Treatment Center of Excellence (CRTCE) in Mississauga, Canada.

Participants received four infusions of IV ketamine over a period of 1 – 2 weeks. The initial two infusions were dosed at 0.5 mg/kg delivered over 40 – 45 min, and the remaining two infusions were dosed at 0.75 mg/kg delivered over 40 – 45 min.

At the 30 min before receiving each infusion participants completed the QIDS-SR16, a self- report measure that characterises their depres sive symptoms. Four questions were used to assess changes in sleep, and the sum of these four questions was used to assess the total sleep improvements.

2.2 | Statistical analyses

This retrospective exploratory analysis was conducted using SPSS®, version 26. A one- way mixed model was used to analyse changes in each individual sleep item across infusions, and a Process macro was used to investigate whether sleep mediated the anti-depressive and anti-suicidal improvements observed in participants.

Age, sex, primary diagnosis and each of the five sleep variables were considered to determine the likelihood that patients would respond or remit to IV ketamine.

3.2 | Mixed model and mediation results

Intravenous ketamine was significantly associated with improvements in insomnia, night-time restlessness, early morning waking, and hypersomnia.

The number of IV ketamine infusions had a significant total effect on the QIDS- SR16 total score, and changes in insomnia symptoms, night-time restlessness, early morning waking, and hypersomnia were significant partial mediators of this relationship.

IV ketamine infusions partially ameliorated depression scores, but not fully. Total sleep improvements mediated this relationship, with an effect size of 0.09.

The number of ketamine infusions had a significant effect on the QIDS-SR16 SI score, and insomnia symptoms, night-time restlessness, early morning waking, and hyper somnia were all significant partial mediators of this relationship.

3.3 | Binomial logistic regression results

A total of 59 patients met the criteria for being a responder or remitter at the post-treatment visit. Patients who had a greater reduction in insomnia symptoms from baseline to endpoint had a greater likelihood of achieving response or remission criteria.

The model accounted for 10% of the variance and showed that greater reduction in restless sleep symptoms was associated with an increased likelihood of achieving response or remission.

The logistic model including early morning waking symptoms was significant, and greater reductions to early morning waking symptoms were a significant predictor of achieving responder or remitter status. The overall sleep total score was the only variable that predicted achieving response or remitter status.

Improvements in sleep were significant partial mediators to the improvements observed in depression severity and symptoms of insomnia in patients receiving IV ketamine. Additionally, improvements in sleep were associated with increased likelihood of achieving response or remission.

Ketamine and sleep-deprivation therapies have similar mechanisms of action, involving regulation of circadian clock transcription factors and normalisation of dysregulated slow-wave activity during sleep. Moreover, evidence suggests that increased inflammatory tone may be a pre-treatment predictor of antidepressant effects in some individuals with MDD receiving ketamine.

The present analysis indicates that chronobiology is a critical domain disturbance that may subserve the behavioural/observational aspects of depression (e.g. suicidality). Ketamine may have a small, but statistically significant, effect on reducing suicidality through improvements in sleep.

The limitations of the present study should be considered when evaluating the results. These limitations include a retrospective analysis, lack of control group, and use of four questions on a scale that may not represent the full phenomenology of sleep deficits.

CONFLICT OF INTEREST

RSM, JDR, KK and YL have received grant support from CIHR, GACD, Chinese National Natural Research Foundation, University of Toronto, Canadian Psychiatric Association, American Psychiatric Association, American Society of Psychopharmacology, Champignon Brands and the Canadian Rapid Treatment Center of Excellence.

AUTHOR CONTRIBUTIONS

Ketamine influences CLOCK:BMAL1 function leading to altered circadian rhythms. Poor subjective sleep quality is associated with risk for death by suicide. Several studies have shown that NMDAR activation regulates the daily rhythms of sleep and mood, and that zolpidem medication may increase the risk of suicide. Ketamine can be used as an antidepressant, and it can also be used to treat depression. Ketamine-induced glutamatergic mechanisms of sleep and wakefulness may be used to treat depression. Associations between sleep duration, melatonin, core body temperature, and depression severity are reported in several studies, including a randomized clinical trial of bright light treatment, fluoxetine, and the combination in patients with nonseasonal major depressive disorder.

Sleep disturbances and suicidal ideation, plans, and attempts in adolescents: a systematic review and meta-analysis. Maj, M., Stein, D. J., Parker, G., Zimmerman, M., Fava, G. A., De Hert, M., McIntyre, R. S., Widiger, T., & Wittchen, H.- U. Insomnia severity is an indicator of suicidal ideation during a depression clinical trial, and the link between suicide and insomnia is theoretically explained. McIntyre, R. S., Berk, M., Brietzke, E., Goldstein, B. I., López-Jaramillo, C., Kessing, L. V., Malhi, G. S., Nierenberg, A. A., Majeed, A., Vieta, E., Vinberg, M., Young, A. H. McIntyre, Millson, Power, and others (2020) found that treatment resistant depression (TRD) was a significant burden on healthcare resources and that repeated intravenous ketamine treatment improved symptoms, suicidal ideation, and functional disability in adults with major depressive disorder and bipolar disorder. Research shows that disturbed sleep is associated with suicidal thoughts and behaviors, and that dopamine plays a role in these disorders.

There are several studies that show that the 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS- C), and self-report (QIDS-SR) are useful for predicting response to ketamine in treatment resistant major depressive disorder and bipolar disorder. Scullin, M. K., Gao, C., Wang, S., Wang, A., Chen, X., Li, Y., Jiang, L., & Zhu, Y. A. (2018). Slow wave sleep and REM sleep contribute to cognitive longevity.

Newly identified sleep-wake and cir cadian circuits as potential therapeutic targets have been reported in several studies.

Intravenous ketamine treatment for treatment- resistant depression is associated with sleep changes that mediate the anti- depressive and anti- suicidal effects.