Depression is a cause of substantial human suffering and considerable cost to society. Pharmacotherapy is used to treat the disorder, but many patients receive no significant benefit from drugs even after weeks or months of use. For such treatment-resistant patients, psychiatric electroconvulsive therapy still remains the most efficacious form of treatment.
An increase of slow EEG activity after seizures has been posited as a factor predicting the effect of electroconvulsive therapy. Already several decades ago, this notion spurred researchers to investigate the antidepressant effect of anaesthesia achieved with isoflurane, but the results were inconclusive.
In more recent studies, ketamine, which blocks NMDA (N-methyl-D-aspartate) receptors, has repeatedly been found to alleviate depressive symptoms rapidly. An effect of similar promptness was observed in a recent clinical study with nitrous oxide (N2O), or laughing gas.
The neurobiological mechanisms underlying the effects of isoflurane and nitrous oxide remain, however, largely unknown. In contrast, an increase in glutamatergic neurotransmission and in the excitability of the cerebral cortex has been suggested as ketamine’s mechanism of action, which is thought to result in changes of synaptic and neuronal function. It has been suggested that these effects originate in the activation of TrkB, a receptor for the BDNF growth factor, and the resulting changes.
Samuel Kohtala looked in his thesis into molecular changes caused by anaesthesia achieved with isoflurane in the mouse hippocampus, observing that urethane, ketamine and many other drugs used as anaesthetics caused similar changes.
Subsequently, Kohtala looked into the effects of nitrous oxide on cellular signalling mechanisms regulated by ketamine in the mouse prefrontal cortex. During exposure to nitrous oxide, the number of markers associated with neural activity grew. After the administration of the gas ended, increased slow EEG activity was observed, during which TrkB-mediated signalling increased in the brain. Ketamine doses sufficient for anaesthesia also increased slow EEG activity and changes in cellular signalling.
“The results indicate a connection between slow EEG oscillations and the changes in cellular signalling linked to ketamine. Therefore, research should now be conducted on whether the excitability of the cerebral cortex and the resulting increase in slow EEG activity are a characteristic shared by rapid-acting antidepressants,” Kohtala states.
____________
Samuel Kohtala's doctoral thesis: "Rapid-acting antidepressants: Shared neuropharmacological mechanisms".