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

Introduction

Sleep disturbance is common in major depressive disorder and bipolar disorder and is linked to broader functional problems such as cognitive impairment. Circadian rhythm dysregulation—indexed clinically by delayed sleep phase, prolonged sleep latency and delayed awakening—has been associated with greater depressive symptom severity, and sleep problems have also been related to suicidal ideation and attempts independent of depression severity. Treatments that target circadian disruption (for example, melatonin receptor agonists, bright-light therapy, and sleep-deprivation therapy) can remit depressive symptoms, but a substantial minority of patients do not respond to conventional monoaminergic antidepressants or chronotherapies, leaving a need for novel mechanistic approaches for treatment-resistant depression (TRD). Preclinical and clinical data suggest repeated-dose ketamine and esketamine have antidepressant effects, and there is convergent evidence that ketamine influences circadian genes and sleep architecture (including reductions in sleep latency, increases in slow-wave sleep, and changes in REM and total sleep), raising the possibility that some of ketamine's clinical benefit could be mediated through sleep-related changes. Rodrigues and colleagues set out to evaluate whether self-reported changes in sleep symptoms mediate the antidepressant and anti‑suicidal effects of repeated intravenous (IV) ketamine in adults with TRD. The study specifically examined whether improvements in four sleep domains (insomnia, night‑time restlessness, early morning waking and hypersomnia), and an aggregate sleep score derived from the QIDS‑SR16, mediated changes in total depressive symptoms and suicidal ideation (SI) across four ketamine infusions delivered in a community clinic setting.