Ketamine-Induced Glutamatergic Mechanisms of Sleep and Wakefulness: Insights for Developing Novel Treatments for Disturbed Sleep and Mood

Abstract

Ketamine, a drug with rapid antidepressant effects and well-described effects on slow wave sleep (SWS), is a useful intervention for investigating sleep-wake mechanisms involved in novel therapeutics. The drug rapidly (within minutes to hours) reduces depressive symptoms in individuals with major depressive disorder (MDD) or bipolar disorder (BD), including those with treatment-resistant depression. Ketamine treatment elevates extracellular glutamate in the prefrontal cortex. Glutamate, in turn, plays a critical role as a proximal element in a ketamine-initiated molecular cascade that increases synaptic strength and plasticity, which ultimately results in rapidly improved mood. In MDD, rapid antidepressant response to ketamine is related to decreased waking as well as increased total sleep, SWS, slow wave activity (SWA), and rapid eye movement (REM) sleep. Ketamine also increases brain-derived neurotrophic factor (BDNF) levels. In individuals with MDD, clinical response to ketamine is predicted by low baseline delta sleep ratio, a measure of deficient early night production of SWS. Notably, there are important differences between MDD and BD that may be related to the effects of diagnosis or of mood stabilizers. Consistent with its effects on clock-associated molecules, ketamine alters the timing and amplitude of circadian activity patterns in rapid responders versus non-responders with MDD, suggesting that it affects mood-dependent central neural circuits. Molecular interactions between sleep homeostasis and clock genes may mediate the rapid and durable elements of clinical response to ketamine and its active metabolite.

Keywords: Brain-derived neurotrophic factor (BDNF); Circadian; Major depressive disorder; Neuroplasticity; Slow wave sleep; Suicidality.

Fig. 1

Slow wave activity (SWA, top) during non-REM episodes (cycles) 1–3 (NR1,2,3) and selected sleep measures (bottom) in patients with major depressive disorder (MDD; n = 30) compared during baseline (BL, grey bars) and the first night (D1) after ketamine infusion (K_D1, black bars). All patients had severe, treatment-resistant MDD at the time of ketamine treatment. The lower panel shows that in patients with MDD, ketamine significantly improved sleep quality [increased Total Sleep (TS), slow wave sleep (SWS), and percent time spent in rapid eye movement sleep (REM %)], and decreased the percent of time spent awake (W%) on D1. Ketamine also increased early production of SWA during NR1, thus enhancing the nighttime decline in SWA across successive non-REM episodes. (* p < 0.05)

Fig. 2

Day 1 and Day 3 patterns of wrist activity for ketamine-treated patients who responded (>50% decrease in Montgomery-Asberg Depression Rating Scale (MADRS) score) within 1 day of ketamine infusion compared with non-responders. (Left panel) Responders (R, red) compared with non-responders (NR, blue) 1 day after ketamine infusion (Day 1). (Right panel) Responders (R, red) who maintained the 50% decrease in MADRS score compared with patients who did not meet response criteria (NR, blue) on Day 3. The raw MADRS scores for each group are shown as inserts for each day. On Day 1, the phase of the 24-h pattern of activity in ketamine responders differed from non-responders (p = 0.0038). On Day 3 the amplitude (p = 0.0488) of the 24-h pattern significantly differed between responders and non-responders. Group sizes are: D1 (R = 21, NR = 30) and D3 (R = 13, NR = 35)