Do sleep changes mediate the anti‐depressive and anti‐suicidal response of intravenous ketamine in treatment‐resistant depression?

Abstract

Summary 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.

Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation

“…Sleep improvements also mediate the effects of ketamine on SI, owing to reductions in insomnia, sleep restlessness, early morning awakening, and nocturnal wakefulness ( Rodrigues et al, 2021 ; Vande Voort et al, 2016 ). Ketamine's sleep-improving effect is likely a multifactorial process involving the normalization of the circadian sleep/wake system.…”

“…Reduced SI by reducing insomnia, sleep restlessness, early morning waking, and nocturnal wakefulness ( Rodrigues et al, 2021 ; Vande Voort et al, 2016 )…”

Modulatory effect of n-3 polyunsaturated fatty acids on depressive-like behaviors in rats with chronic sleep deprivation: potential involvement of melatonin receptor pathway and brain lipidome

“…10 Furthermore, persistent insomnia was reported to be a predictor of depression relapse and may contribute to refractory depression. 11 A meta-analysis review revealed that poor sleep quality, defined as an individual having shorter or longer sleeping times than normal, may increase the risk of morbidity related to depression. 12 These findings indicate that sleep disturbance can be considered a potential therapeutic target for improving the symptoms and progression of psychiatric disorders.…”

Subanesthetic Dose of Ketamine Administered Before Each Electroconvulsive Therapy Session Improves Antidepressant and Sleep Quality Outcomes

“…12 Researchers have found that the antidepressant effects of ketamine were associated with decreased wakefulness, increased slow-wave activity, total sleep, and rapid eye movement sleep in MDD patients. 13 Ketamine infusions induced better therapeutic effects in sleep responders than in sleep nonresponders and patients without sleep disturbances. 14 Scholars found that improvement of sleep quality may be related to rapid improvement in depressive symptoms.…”