Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia.

Ketamine's rapid antidepressant effects are linked to increased glutamate signaling and synaptic plasticity in the prefrontal cortex, with activation of the BDNF receptor TrkB as a key event. The mechanisms behind ketamine's effects on TrkB remain unclear. Nitrous oxide, another rapid antidepressant, activates TrkB signaling after its acute effects have faded, coinciding with increased slow delta frequency EEG activity. Various anesthetics and sedatives also activate TrkB signaling, suggesting that rapid-acting antidepressants may share the ability to regulate TrkB during homeostatically evoked slow-wave activity, which may be important for sustained antidepressant effects. This work urges examining brain physiology and temporally distributed signaling patterns beyond conventional receptor pharmacology.

Study at a glance

Abstract

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2 O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.